Triphenylalkyl antimicrobial agents

ABSTRACT

The invention relates to triphenylalkyl antibacterial compounds of the general formula: ##STR1## pharmaceutical compositions containing the compounds, and methods for their production and use. These compounds are effective in inhibiting the action of a bacterial histidine protein kinase and are thus useful as anti-infective agents against a variety of bacterial organisms, including organisms which are resistant to other known antibiotics.

This is a Continuation-in-Part, of application Ser. No. 08/459,446,filed Jun. 2, 1995, now U.S. Pat. No. 5,643,950.

FIELD OF THE INVENTION

The invention relates to triphenylalkyl antibacterial compounds,pharmaceutical compositions containing the compounds, and methods fortheir production and use. These compounds are effective in inhibitingthe action of a bacterial histidine protein kinase and are thus usefulas anti-infective agents against a variety of bacterial organisms,including organisms which are resistant to other known antibiotics.

BACKGROUND OF THE INVENTION

Prokaryotes regulate the transcription of many of their genes inresponse to changes in the organisms' environment (J. B. Stock, A. M.Stock, and J. M. Mottonen, Nature, 344, 395-400 (1990)). Such regulationis essential if the organism is to adapt itself to survival in achanging environment, and pathogenic bacteria rely on such regulatorysystems to enable them to survive within their host's body (J. F.Miller, J. J. Mekalanos, S. Falkow, Science, 243, 1059 (1989)). Chemicalcompounds that interfere with the regulatory mechanisms would beexpected to be useful anti-infective drugs, as they would preventbacteria from making necessary adaptive changes in their patterns ofgene expression.

Virulence, chemotaxis, toxin production, sporulation, and reproductionare examples of the bacterial processes that are under regulatorycontrol, and which could be inhibited by such compounds. The inhibitionof one or more of these processes is expected to lead to reducedvirulence, a slowing or halting of bacterial growth and reproduction,and even to bacterial cell death if vital functions are interrupted.

For example, it has been shown that Salmonella species express certainproteins, under regulatory control and in response to the presence ofintestinal epithelial cells, which enable them to adhere to and invadethese cells. Bacteria unable to synthesize these proteins are avirulent:they cannot cause infection in mice (B. B. Finlay, F. Heffron, S.Falkow, Science, 243, 940-943 (1989)). A similar effect would beexpected if the genes coding for these proteins were intact, butremained unexpressed.

To accomplish adaptive responses to the environment, bacteria rely onphosphorelay mechanisms, referred to in the art as "two-componentswitches." These switches have the net effect of transmittinginformation from the environment to the cell nucleus, where theinformation is responded to by the switching on or off of transcriptionof relevant genes. The first step of this phosphorelay scheme relies onnumerous histidine protein kinase (HPK) enzymes. Most of these HPKenzymes are sensor molecules, and respond to stimulation by specificenvironmental signals by transferring phosphate from ATP to a histidineresidue of the HPK protein. Some HPK enzymes are stimulated by thepresence of acceptor proteins (described below), the concentration ofwhich are modulated by environmental signals. In either case, thisauto-phosphorylation is followed by transfer of the phosphate to anaspartyl residue of one or more acceptor proteins (the second componentsof the two-component switch), which are either regulators of geneexpression (by binding to control regions on DNA, or to the RNApolymerase complex) or are themselves kinases for other acceptormolecules. These secondary acceptors may again be regulatory proteins,or kinases toward yet another protein. This cascade of phosphate fromprotein to protein eventually results in the phosphorylation of one ormore regulatory proteins, which then control gene expression.

Mammalian cells do not, or at least are not presently known to, utilizeHPK-driven phosphorelay systems for gene regulation. Thus, compoundswhich selectively inhibit either the autophosphorylation of the HPKprotein, or the phosphotransfer step(s), or both, would not be expectedto have undesirable effects on the host organism, and are promisingcandidates for antiinfective drugs. The emergence of drug-resistantpathogenic organisms that are resistant to one or more of the currentlyavailable drugs has created a need for novel antibiotics, that act bymechanisms unrelated to those of currently available agents, andinhibitors of HPK would fill this need. The presence of multipleHPK-driven systems (over fifty are currently known) in bacteria givesHPK inhibitors a potential advantage over current antibiotics, in thatmutations of a single HPK enzyme are unlikely to confer drug resistanceto an organism.

Recently, workers in this field reported a method for detectingbacterial "virulence" genes that are selectively expressed when bacteriainfect a host (M. J. Mahan, J. M. Slauch, and J. J. Mekalanos, Science,259, 686-688 (1993)). The potential use of this information in thedesign of new antibiotics was mentioned, but actual methods of reducingexpression of these genes were not described. A preliminary report fromanother group of workers disclosed inhibitors of the two-componentswitch controlling alginate gene activation in Pseudomonas aeruginosa inan in vitro system (S. Roychoudhury et al., Proc. Nat. Acad. Sci., 90,965-969 (1993)), but no anti-bacterial activity of the compounds wasreported.

SUMMARY OF THE INVENTION

The invention comprises compounds of the general structure 1 shownbelow: ##STR2## wherein Z¹, Z², and Z³ are independently H, halogen, C₁-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, or nitro;

m is an integer from 1-5;

X is CH₂ O, CH₂ S, CH₂ NR, C(O)NR, CH₂ OC(O)CH₂, or CH₂ OC(O)CH₂ CH₂ ;

Ar is aryl optionally substituted with one to three substituents,selected from halogen, hydroxy, C1-C6 alkyl and C1-C6 alkoxy;

W is oxygen, sulfur, or a bond;

n is an integer from 0-5;

A is:

(a) NR¹ R² ;

(b) N⁺ R¹ R² R³ B⁻ ;

(c) a moiety of the formula: ##STR3## (d) CO₂ H; (e) CH(R⁴)CO₂ H;

(f) CH═CHR⁵ ;

(g) CH═C(CO₂ H)₂ ;

(h) 5-tetrazolyl;

(i) a moiety of the formula: ##STR4## (j) heterocycle optionallysubstituted with 1-3 substituents selected from C1-C6 alkyl, andaryl-C1-C6 alkyl;

R, R¹, R², and R³ are independently H, C1-C6 lower alkyl, or aryl-C1-C6alkyl;

R⁴ is hydrogen or hydroxy;

R⁵ is:

(a) CO₂ H; or

(b) C(O)NH(CH₂)_(p) OH, wherein p is an integer from 1-4;

B⁻ is a pharmaceutically acceptable counterion;

R₆ and R₇ are independently hydrogen, C1-C6 loweralkyl, aryl(C1-C6)alkylor t-butoxycarbonyl or R₆ and R₇ taken together form an imidazoline,imidazolyl or pyrimidine ring;

wherein aryl is phenyl, biphenyl or naphthyl;

wherein heterocycle is a saturated or unsaturated, charged or uncharged5 or 6 membered monocyclic ring which has 1, 2, or 3 oxygen, nitrogen orsulfur atoms;

with the provisos that:

where n is 0, A may also be hydroxy;

where X is C(O)NH, A is not CO₂ H; and

where n is 0, A is not NH_(2;)

where n is 0 or 1, and W is O or S, A is not OH, NR¹ R², N⁺ R¹ R² R³ B⁻or guanidino;

and the pharmaceutically acceptable salts and prodrug forms thereof.

Another aspect of the invention comprises a method of treating bacterialinfections in mammals by administering to a mammal suffering from suchinfection a therapeutically effective amount of a compound effective ininhibiting the action of a bacterial histidine protein kinase. Moreparticularly, the invention involves a method of treating bacterialinfections by inhibiting the autophosphorylation of bacterial histidineprotein kinase A or inhibiting the transfer of phosphate fromphosphorylated histidine kinases to the aspartyl residue of phosphateacceptor proteins involved in regulation of bacterial gene expression,particularly the operon protein Spo0F.

The compounds of the present invention inhibit the autophosphorylationof bacterial histidine kinases; they also inhibit the transfer ofphosphate from phosphorylated histidine kinases to the aspartyl residuesof the phosphate acceptor proteins involved in regulation of bacterialgene expression. The compounds of the present invention have been foundto inhibit the growth of bacteria by the standard method, measurement ofminimum inhibitory concentrations (MIC values). The compounds are usefulas bacteriostatic and bactericidal agents, and as anti-infective agentsin the treatment of infectious diseases. They may also have utility inincreasing the sensitivity of bacteria to conventional antibiotics.

Preferred embodiments of the invention are the compounds where X is CH₂O or CH₂ S, Ar is phenylene, and where A carries a charge atphysiological pH. More preferred are the embodiments where A is amino,guanidino, or comprises a quaternary nitrogen.

DETAILED DESCRIPTION OF THE INVENTION

Relative to the above generic description, certain compounds of FormulaI are preferred.

Preferred groups for X are CH₂ O and CH₂ S.

Preferred groups for Ar are 1,2-phenylene, 1,3-phenylene, 1,4-phenylene,1,6-naphthylene, 6,1-naphthylene, 1,5-naphthylene, 2,5-naphthylene,5,2-naphthylene, or 2,6-naphthylene.

Preferred groups for A are NR¹ R², guanidino, CO₂ H, 5-tetrazolyl,CH═CHCO₂ H, CH═CHC(O)NHCH₂ CH₂ OH, CH(OH)CO₂ H, CH═C(CO₂ H)₂, N⁺ R¹ R²R³ B⁻, and moieties of the formulae: ##STR5## particularly those whichcarry a charge at physiological pH.

Most preferred of the compounds of Formula I are those in which:

X is selected from CH₂ O, and CH₂ S;

Ar is selected from 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene;

Ar may optionally be further substituted with one to three substituentsselected from halogen, C1-C6 alkyl, hydroxy, or C1-C6 alkoxy;

n is 1, 2, or 3;

m is 1 or 2;

W is 0 or a bond; and

A is selected from NR¹ R², guanidino, and N⁺ R¹ R² R³ B⁻ wherein R¹, R²,and R³ are independently selected from H,

C1-C6 lower alkyl, or aryl-C1-C6 alkyl, and wherein B⁻ is apharmaceutically acceptable anion.

The compounds of the present invention are prepared in accordance withthe methods described below and illustrated in the following Schemes.The key step in the synthetic sequence, when X is CH₂ O or CH₂ S, isshown in Scheme 1, and is usually a Mitsunobu reaction between theappropriately substituted triarylalkanol (2, L=OH) and the appropriatelysubstituted aryl compound 3, wherein B is is the moiety A, a protected Amoiety or a precursor for A as described below and in Scheme 2. Analternative to the Mitsunobu method is the reaction of 2, wherein L ishalide, sulfonate, or another appropriate leaving group, with the arylcompound 3 in the presence of a suitable base, such as sodium hydride,sodium hydroxide, or potassium carbonate. ##STR6##

The Mitsunobu reaction may be one of several variants known in the art;the selection of the appropriate phosphine, azodicarbonyl reagent, andsolvent will be at the discretion of the practitioner, based onpublished precedents and on empirical results with the particularcombination of substrates to be coupled. Guidance can be found in thereview article by D. L. Hughes, in Organic Reactions, 42, 335-656(1992), and in the detailed examples below. In most casestriphenylphosphine (Ph₃ P) and diethylazodicarboxylate (DEAD), oralternatively tributylphosphine (Bu₃ P) and (azodicarbonyl)dipiperidine(ADDP), will suffice. Alternatively, displacement of a halide or otherleaving group by the appropriate phenoxide or thiophenoxide can be usedto generate the CH₂ O or CH₂ S linkers.

At the time of the Mitsunobu reaction, the group A will in most caseshave to be in a protected form B, or else (for instance when A is aheterocyle) B will be a precursor functional group convertible into thedesired heterocycle or other group A. Once the linker X has beenestablished, the group B is converted, if necessary, into the desiredgroup A, as shown in Scheme 2. Suitable protecting groups for guanidinesand amines include, but are not limited to, trifluoroacetyl,t-butoxycarbonyl (Boc), and benzyloxycarbonyl. The case where Ar is1,4-phenylene is shown in Scheme 2 for purposes of illustration only;the chemical processes presented in the scheme are in general applicableto all definitions of Ar.

Suitable protecting groups for carboxylic acids include, but are notlimited to, lower alkyl esters or benzyl esters; suitable precursorgroups include olefin, nitrile, or oxazolidine. For cases where B=NHBoc,NHC(═NBoc)NHBoc, CO₂ R, or CH═CHCO₂ R, the intermediates are deprotectedafter the Mitsunobu reaction to afford amines, guanidines or carboxylicacids, respectively. For cases where B=CN, the nitrile may be hydrolyzedto a carboxylic acid, reduced to provide an amine, or converted to atetrazole; where B=an olefin, it may be oxidized with ozone or otherreagents to provide an aldehyde or acid. Where B=CHO, NHBoc, CO₂ R, orCH═CHCO₂ R, the compounds may be converted into those of structure 1where A is one of the heterocycles described. In the cases where A is apiperidine or piperazine, the terminal nitrogen is protected during theMitsunobu reaction in the manner described above for amines. ##STR7##

Where B=CHO, reduction to the corresponding alcohol and subsequentconversion to the chloride (1, A=Cl) followed by reaction with anitrogen-containing heterocycle permits preparation of quaternaryheterocyclic values of A, such as the pyridinium and imidazoliumderivatives exemplified below. The chloride can also be used toquaternize tertiary aliphatic amines, giving 1 where A=N⁺ R¹ R² R³, ormay be reacted with primary or secondary amines to give cases whereA=NR¹ R². Compounds where B=CHO are also useful precursors to acids viaoxidation, to alcohols via reduction, to the phenol (if n=0 and W is abond) by Baeyer-Villiger oxidation, and to alpha-hydroxy acids(A=CH(OH)COOH) via addition of trihalomethyl anions. Specific examplesof these processes are to be found below.

In cases where X=C(O)NR or CH₂ OC(O)(CH₂)p, a coupling reaction togenerate the linker X is performed with the appropriately substitutedacid and the appropriately substituted aniline or alcohol derivative. InSchemes 3 and 4, examples where Ar is 1,4-phenylene are illustrated, butthe methods are applicable to any definition of Ar. As with theMitsunobu reaction, it will sometimes be necessary that group B is aprecursor or protected form of group A, as defined as in Scheme 2, andis subsequently converted into the desired group A as in Scheme 2. Ingeneral, the carboxylic acid partner of the coupling reaction isactivated with one of a variety of reagents, such as carbonyldiimidazole(CDI), thionyl chloride, oxalyl chloride, or a carbodiimide reagent suchas dicyclohexylcarbodiimide (DCC). The coupling reactions may be chosenfrom, but are not limited to, the ones illustrated in the scheme anddescribed further below. There are a wide variety of coupling methodsknown to one skilled in the art, and the majority of them would beapplicable to the reactions in Schemes 3 and 4.

The starting materials for the Mitsunobu and acylation couplingreactions of Schemes 3 and 4 are, in general, known classes ofcompounds, and are prepared by routine methods, illustrated in Schemes 5and 6. In Scheme 5, the triarylalkanoic acid and triarymethane startingmaterials are in some cases commercially available, others can beprepared by various published methods (J. W. Wilt, J. A. Lundquist, J.Org. Chem., 29, 921 (1964); W. H. Starnes Jr., J. Org. Chem., 33, 2767(1968). The conversion of the acids to triarylalkanols by boranereduction is a known synthesis (M. Said et al., Biochem. Biophys. Res.Comm., 187, 140-145 (1992)), modified in the present case by theaddition of trimethyl borate to accelerate the reaction. Thechain-extension of a triarylalkanol to the next-higher triarylalkanoicacid then makes the next higher value of m accessible (McPhee,Lindstrom, J. Amer. Chem. Soc., 65, 2177 (1943). The triarylalkanols mayalso be prepared from the corresponding triarylmethanes as shown (C. G.Screttas, M. Micha-Screttas, J. Org. Chem., 47, 3008-3011 (1982), alsoH. W. Gibson et al., J. Org. Chem., 58, 3748-3756 (1993)). The variousgroups Z are compatible with one or more of these synthetic approaches.Alternatively, the triarylalkanoic acid can be prepared and thennitrated, and the resulting isomers separated by chromatography. Thenitro groups can be reduced to amino, and then via diazotization tohalogen, hydroxy, or alkoxy groups.

In Scheme 6, reaction of 2-(4-hydroxyphenyl)ethylamine withdi-t-butyldicarbonate, to afford a protected phenolic coupling componentfor the Mitsunobu reaction, is illustrated. A variety of(hydroxyphenyl)alkylamines and (hydroxyphenoxy)alkylamines arecommercially available or are known compounds; they can be synthesizedby common methods such as reductive amination of benzaldehydes,hydrogenation of arylacetonitriles or aryloxyacetonitriles, reduction ofcinnamides or cinnamylamines, etc. Methods for their preparation can bechosen from, but are not limited to, the examples presented herein.Where X is to be CH₂ S, 4-mercaptobenzaldehyde may be coupled via theMitsunobu reaction to the desired triarylalkanol, and the aldehyde thenconverted to the desired group (CH₂)_(n) -A or (CH₂)_(n) -B by themethods discussed below.

Also in Scheme 6, the generation of a protected guanidine from thecorresponding amine is illustrated, again providing a phenolic componentfor the Mitsunobu coupling. The illustrated use ofN,N'-bis(t-butoxycarbonyl)-S-methylisothiourea for this purpose is aknown procedure (R. J. Bergeron, J. S. McManis, J. Org. Chem., 52,1700-1703 (1987), it is in some cases improved by the addition of silveracetate to the reaction mixture. (See also M. S. Bernatowicz, Y. Wu, G.R. Matsueda, Tetrahedron Letters, 34, 3389 (1993)). These methods are ingeneral applicable to all amines with the various definitions of Ar, X,W, and n.

Alternatively, one can prepare 1 with A=NH₂ and then convert the aminogroup into a guanidino group by the above or by other known methods(e.g., M. S. Bernatowicz, Y. Wu, G. R. Matsueda, J. Org. Chem., 57,2497-2502 (1992) and references therein). ##STR8##

Scheme 7 illustrates the preparation of compounds where A=CO₂ H, andconversion of these to N-(hydroxyalkyl)amides, followed by cyclizationto give the claimed oxazolidine or dihydro-oxazine derivatives. Thestarting omega-(hydroxyphenyl)alkanoic esters (or the correspondingacids) in Scheme 7 are known compounds; novel examples with furthersubstitution on the ring can be prepared as described further below, orby other methods known to the art. For example, beginning withoptionally substituted 4-hydroxy or 4-methoxy benzaldehydes, one canobtain the case where n=0 by oxidation (B. O. Lindgren, T. Nilsson, ActaChem. Scand., 27, 888 (1973)), where n=1 by chain extension (K. Shaw, M.Armstrong, A. McMillan, J. Org. Chem., 21, 1149 (1956)) where n=2 bycondensation with malonic acid to give the cinnamic acid (J. Koo et al.,Org. Syn. coll. vol. IV, 327 (1963)), followed by hydrogenation ifdesired, and where n=3 by homologation with a phosphorous ylide (J. G.Cannon et al., J. Med. Chem., 32, 2210 (1989)), again followed byhydrogenation if desired. As shown in Scheme 8, these reactions can alsobe performed on 1 where A=CHO, giving the corresponding acids directly;these methods are also applicable to the other disclosed definitions ofAr.

Where n is 0 and A is CHO, one may perform a Baeyer-Villiger oxidationon 1 to obtain the phenol wherein n is 0 and A is OH, and thenO-alkylate this phenol via appropriate Mitsunobu or nucleophilicdisplacement reactions as described above to attach the group (CH₂)_(n)A or (CH₂)_(n) B, thereby obtaining the cases where W is oxygen.Alternatively, one can submit the known compounds2-(phenylsulfonyloxy)phenol or 3-(phenylsulfonyloxy)phenol to thereactions of Scheme 1, and then remove the phenylsulfonyl group byhydrolysis. Examples of both approaches to the cases where W is oxygenare provided below.

Where it is desired that W be sulfur, a suitable precursor group isnitro. For example, one would submit 4-nitrophenol to the Mitsunobureaction of Scheme 1, generating an intermediate where n =0 and B is anitro group. Reduction, diazotization and reaction with a xanthate (theLeuckart thiophenol synthesis, see D. S. Tarbel, J. Amer. Chem. Soc.,74, 48 (1952)), provides the thiophenol, and alkylation with analkylating agent such as Br(CH₂)_(n) A or Br(CH₂)_(n) B then providesaccess to the desired material. ##STR9##

The foregoing reactions are performed in a solvent appropriate to thereagents and materials employed and suitable for the transformationbeing effected. It is understood by those skilled in the art of organicsynthesis that the various functionalities present on the molecule mustbe consistent with the chemical transformations proposed. This willfrequently necessitate judgment as to the order of synthetic steps,protection of reactive groups, and selection of reaction conditions.Reaction conditions compatible with the substituents employed will beapparent to one skilled in the art, as will be the selection ofprotecting groups where needed.

From formula 1 it is evident that some of the compounds of the inventionmay have one or more asymmetrical carbon atoms in their structure. It isintended that the present invention include within its scope thestereochemically pure isomeric forms of the compounds as well as theirracemates. Stereochemically pure isomeric forms may be obtained by theapplication of art known principles. Diastereoisomers may be separatedby physical separation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diasteromeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

Suitable pharmaceutical salts are those of inorganic or organic acids,such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, phosphoric acid, acetic acid, succinic acid, oxalicacid, malic acid and the like. Suitable salts are also those ofinorganic or organic bases, such as KOH, NaOH, Ca(OH)₂, Al(OH)₃,piperidine, morpholine, ethylamine, triethylamine and the like.

Also included within the scope of the invention are the hydrated formsof the compounds which contain various amounts of water, for instance,the hydrate, hemihydrate and sesquihydrate forms.

The ability of bacteria to quickly respond to changes in the environmentis of utmost importance for their survival. Bacteria are capable ofrapidly responding and adapting to such diverse stimuli as changes innutrients, osmolarity, temperature, light, or host environment. Theseresponses may be transient, such as those required for changes inmotility or for entry into a host cell. Alternatively, the responses mayrequire major shifts in gene expression and cell morphology, such asthose required for sporulation, or for survival within a macrophage. Themechanism by which bacteria are able to sense cues from the physicalenvironment (or from within the cytoplasm) and process these signalsinto appropriate responses often involves the so-called "two-component"systems.

As stated above, the treatment method of the present invention is basedon the inhibition of this "two-component switch" system. All bacteriause this mechanism to control various adaptive/virulence factors tofacilitate establishment of a bacterial population in the environment(for example, a bacterial infection in a host). The system invariablyconsists of a sensor which either activates a kinase or is a part of thekinase, and which upon stimulation, autophosphorylates. Thisphosphorylated species is a highly active phosphodonor which immediatelytransfers its phosphate to a "regulatory" component, which in turninitiates the biological response such as transcription or furtherphosphotransfer in a cascade which eventually ends in regulation ofbacterial gene expression. Although each of the kinases and responseregulators has a unique sequence (in fact, even functionally identicalproteins have slightly different sequences in different species) theyshare a homologous biochemical mechanism and they share significanthomology in the active site.

As stated, the present invention provides compounds which exhibitantibiotic activity by inhibiting the autophosphorylation of bacterialhistidine kinases. They also inhibit the transfer of phosphate fromphosphorylated histidine kinases to the aspartyl residues of thephosphate acceptor proteins involved in regulation of bacterial geneexpression.

This invention further provides a method of treating bacterialinfections, or enhancing the activity of other antibacterial agents, inwarm-blooded animals, which comprises administering to the animals acompound of the invention alone or in admixture with a diluent or in theform of a medicament according to the invention.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents, and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing for example, from about 0.5% to 5% of suspendingagent, syrups containing, for example, from about 10% to 50% of sugar,and elixirs containing, for example, from about 20% to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5% to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

Compositions for topical application may take the form of liquids,creams or gels, containing a therapeutically effective concentration ofa compound of the invention admixed with a dermatologically acceptablecarrier.

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Solid carriers include starch,lactose, dicalcium phosphate, microcrystalline cellulose, sucrose andkaolin, while liquid carriers include sterile water, polyethyleneglycols, non-ionic surfactants and edible oils such as corn, peanut andsesame oils, as are appropriate to the nature of the active ingredientand the particular form of administration desired. Adjuvants customarilyemployed in the preparation of pharmaceutical compositions may beadvantageously included, such as flavoring agents, coloring agents,preserving agents, and antioxidants, for example, vitamin E, ascorbicacid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacological acceptable salt can be prepared in watersuitably mixed with a surfactant such as hydroxypropyl-cellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.1 mg/kg to about 400mg/kg of animal body weight, preferably given in divided doses two tofour times a day, or in sustained release form. For most large mammalsthe total daily dosage is from about 0.07 g to 7.0 g, preferably fromabout 100 mg to 1000 mg Dosage forms suitable for internal use comprisefrom about 100 mg to 500 mg of the active compound in intimate admixturewith a solid or liquid pharmaceutically acceptable carrier. This dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation.

The production of the above-mentioned pharmaceutical compositions andmedicaments is carried out by any method known in the art, for example,by mixing the active ingredients(s) with the diluent(s) to form apharmaceutical composition (e.g. a granulate) and then forming thecomposition into the medicament (e.g. tablets).

The compounds of the present invention have antibacterial activity asdetermined by the following tests. First, the compounds were tested fortheir activity in inhibiting the autophosphorylation of Kinase A and thetransphosphorylation of Spo0F, two proteins involved in one of the abovedescribed signal transduction systems controlling gene expression inbacteria. Representative compounds were then tested for antibacterialactivity against selected organisms by the standard MIC method. Theresults are set forth below.

Table 1 lists examples of compounds of the invention, along with theirIC₅₀ values in the HPK in vitro assay described below, and MIC valueranges for the selected microorganisms identified below. These examplesare merely illustrative of the invention, and are not intended to limitthe scope of the claims in any way. In the table, the first locant ofeach Ar group is the carbon bearing the substituent --X--; the secondlocant refers to the carbon bearing the substituent --W--.

                                      TABLE 1    __________________________________________________________________________                                                   IC.sub.50                                                      MIC    Ex. #       Z.sup.1, Z.sup.2, Z.sup.3            m X      Ar        W n A               (μM)                                                      (μg/mL)    __________________________________________________________________________     1 H, H, H            1 CONH   1,4-phenylene                               --                                 0 1-piperazinyl   200     2 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0                                    ##STR10##      170     3 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 2 NH.sub.2        14 2-4     4 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1 NH.sub.2        19     5 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 2 NH(NH)NH.sub.2   5 1-2     6 Cl, Cl, Cl            1 CH.sub.2 O                     1,4-phenylene                               --                                 2 NH2             150     7 H, H, H            1 CH.sub.2 O                     1,3-phenylene                               --                                 2 NH2             80     8 H, H, H            1 CH.sub.2 O                     6-OMe-1,3-phenylene                               --                                 2 NH2             27 4     9 Cl, Cl, Cl            1 CH.sub.2 O                     1,4-phenylene                               --                                 2 NH(NH)NH.sub.2  21 8    10 H, H, H            3 CH.sub.2 O                     1,4-phenylene                               --                                 2 NH(NH)NH.sub.2  15 2-4    11 H, H, H            2 CH.sub.2 O                     1,4-phenylene                               --                                 2 NH(NH)NH.sub.2  21    12 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 2 COOH            51 2-16    13 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1 COOH            50 8-16    14 H, H, H            1 CH.sub.2 S                     1,4-phenylene                               --                                 2 COOH            34 4-8    15 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 3 COOH            14 8-64    16 H, H, H            1 CONH   1,4-phenylene                               --                                 2 NH2             59 32-64    17 H, H, H            1 CH.sub.2 O                     2,6-naphthylene                               --                                 0 COOH            300                                                      4-64    18 H, H, H            1 CONH   1,4-phenylene                               --                                 2 NH(NH)NH.sub.2  51 4-16    19 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 2                                    ##STR11##      260    20 H, H, H            1 CH.sub.2 O                     2,6-naphthylene                               --                                 1 NH2             75 4-8    21 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0 COOH            290                                                         8->128    22 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0 t-CHCHCOOH      71 4-64    23 H, H, H            1 OC(O)CH.sub.2                     1,4-phenylene                               --                                 0 OH              170                                                      >128    24 H, H, H            1 OC(O)(CH.sub.2).sub.2                     1,4-phenylene                               --                                 0 OH              160                                                      >128    25 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0                                    ##STR12##      150                                                      >128    26 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 2                                    ##STR13##      43 8-16    27 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 2                                    ##STR14##      11 8-64    28 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1 N.sup.+ (Me).sub.2 CH.sub.2 Ph                                                   13    2    29 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1                                    ##STR15##       6 2-4    30 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1                                    ##STR16##      28 2-8    31 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0 CH(COOH).sub.2  54 >128    32 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1                                    ##STR17##      19 8-64    33 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 1 N.sup.+ (Me).sub.3                                                   29 4-8    34 H, H, H            1 CH.sub.2 O                     1,3-phenylene                               --                                 1 COOH            38    32    35 H, H, H            1 CH.sub.2 O                     1,3-phenylene                               --                                 2 COOH            42  4-128    36 H, H, H            1 CH.sub.2 O                     1,2-phenylene                               --                                 1 COOH            45 16-32    37 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0 CH(OH)COOH      73   32->128    38 H, H, H            1 CH.sub.2 O                     1,2-phenylene                               --                                 2 COOH            27    39 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0                                    ##STR18##      110    40 H, H, H            1 CH.sub.2 S                     1,4-phenylene                               --                                 3 NH2             13    41 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               --                                 0                                    ##STR19##      18    42 H, H, H            1 CH.sub.2 O                     3-OH-1,2-phenylene                               --                                 0 COOH            85    43 H, H, H            1 CH.sub.2 O                     1,3-phenylene                               --                                 0 t-CHCHCOOH      40    44 H, H, H            1 CH.sub.2 O                     1,3-phenylene                               O 1 COOH            71    45 H, H, H            1 CH.sub.2 O                     1,2-phenylene                               O 1 COOH            20    46 H, H, H            1 CH.sub.2 O                     1,3-phenylene                               O 3 COOH            16    47 H, H, H            1 CH.sub.2 O                     1,2-phenylene                               O 3 COOH    48 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               O 1 COOH    49 H, H, H            1 CH.sub.2 O                     1,4-phenylene                               O 3 COOH    __________________________________________________________________________

The protocols for the above referenced assays are as follows.

1. Autophosphorylation of Kinase A and Transphosphorylation of Spo0FAssay

To study the effect of the compounds of the present invention on thesignal transduction process in bacteria, the inhibiting effect of thecompounds on the sporulation operon proteins Kinase A and Spo0F wasexamined. Specifically, the inhibition of autophosphorylation of KinaseA and the transphosphorylation of Spo0F was determined in the followingassays. The Spo0F response regulator is the primary substrate forphosphorylation by the protein kinase, Kin A, involved in thesporulation process in bacteria. See D. Burbulys, K. A. Trach, J. A.Hoch, Cell, 64, 545-552 (1991). Spo0F and KinA were prepared fromrecombinant E. coli overexpressing the proteins (J. Cavanagh et al,Amino Acids, 6, 131-140 (1994) and references therein).

The following stock reagents were either prepared and used promptly orstored at the indicated temperature:

8 X Salts : 2M KCl (5 mL), 1M MgCl₂ (800 mL), 1M CaCl₂ (100 mL), 10mg/mL phenylmethylsulfonyl fluoride (200 mL), 1 M dithioreitol (50 mL),0.25M Na₂ EDTA (32 mL) and H₂ O mL (-20° C.)

5×Loading Dye: 0.5M TRIS-HCl-pH 6.8 (7.5 mL), 10% SDS (2 mL) 0.1%bromophenol blue (0.5 mL), 100% glycerol (3 mL) and 12.5 M2-mercaptoethanol (0.3 mL)

1-1.3 mg/mL KinA:15 mM TRIS-HCl, pH 8.0, 6 mM KCl; 4 mM2-mercaptoethanol; 40% glycerol (-20° C.)

1 mg/mL Spo0F: 17.5 mM TRIS-HCl, pH 8.0; 0.7 mM KCl ; 0.7 mM MgCl₂ ; 0.7mM CaCl₂ ; 5mM 2-mercaptoethanol; 30% Glycerol (-20° C.)

5% Stacking Gel: 40% 29:1 acrylamide:bis acrylamide (1.25 mL), 0.5MTRIS-HCl, pH 6.8 (2.5 mL), 10% SDS (0.1 mL), D-H₂ O (6.15 mL) 10%ammonium persulfate (100 mL) and TEMED (25 mL) SDS Running Buffer:TRIS-BASE (3.02 g), glycine (14.4 g) SDS (1 g), D-H₂ O (to 1L)

The reaction mixture was prepared from 8×Salts (87 μL), 1M TRIS, pH 8(118 μL), 50% glycerol (63 μL), Spo0F (14.1 μL) and KinA (7.0 μL).Microcentrifuge tubes were charged with the reaction mixture (18.5 μL)and a 1.0 mM solution of the test compound in 5% DMSO (18.5 μL), andincubated for 15 min on ice. 100 mM ATP solution (3.0 μl, containing 625μCi ³² P!ATP) was added, and the mixture left for 10 minutes at roomtemperature. The reaction was quenched with 5×loading dye (10 μL pertube) and the samples were loaded on a prepared 5% Stacking Gel, orstored on dry ice until ready for use. The prepared wells were filledwith SDS Running Buffer, samples were loaded into the wells, and 80volts were applied to the gel until the dye front reached the bottom ofthe stacking gel. The voltage was then increased to 250 volts untilelectrophoresis was complete. Radioactive bands in the gel correspondingto phosphorylated KinA and Spo0F were imaged and quantitated with aphosphoimager.

If either enzyme was inhibited (as evidenced by the absence of labelledprotein in the developed gel), an IC₅₀ was calculated by running theassay with a range of inhibitor concentrations from 1 to 500 μM. Afterelectrophoresis of the reaction mixtures, percent inhibition wasdetermined by measuring the concentration of radioactive phosphorus witha phosphoimager and calculating the values using a software program(BioRad Molecular Analyst).

2. MIC Anitimicrobial Assay

The in vitro antimicrobial activity of the compounds was determined bythe microdilution broth method following the test method from theNational Committee for Laboratory Standards (NCCLS). This method isdescribed in the NCCLS Document M7-A2, Vol.10, No.8 "Methods forDilution Antimicrobial Susceptibility Test for Bacteria that GrowAerobically--Second Edition."

In this method two-fold serial dilutions of drug in cation supplementedMueller-Hinton broth are added to wells in microdilution trays. The testorganisms are prepared by adjusting the turbidity of actively growingbroth cultures so that the final concentration of test organism after itis added to the wells is approximately 5×10⁴ CFUs/well).

Following inoculation of the microdilution trays, the trays areincubated at 35° C. for 16-20 hours and then read. The MIC is the lowestconcentration of test compound that completely inhibits growth of thetest organism. The amount of growth in the wells containing the testcompound is compared with the amount of growth in the growth-controlwells (no test compound) used in each tray.

The following examples describe in detail the chemical synthesis ofrepresentative compounds of the present invention. The procedures areillustrations, and the invention should not be construed as beinglimited by chemical reactions and conditions they express. No attempthas been made to optimize the yields obtained in these reactions, and itwould be obvious to one skilled in the art that variations in reactiontimes, temperatures, solvents, and/or reagents could increase theyields.

Methods of preparing the exemplified compounds of the invention arepresented below. These examples are intended to illustrate the methodsof synthesis, and are not intended to limit the scope of the claims inany way. Abbreviations used: DEAD, diethyl azodicarboxylate; Ph₃ P,triphenylphosphine; Bu₃ P, tri-n-butylphosphine; THF, tetrahydrofuran;DMF, N,N-dimethylformamide; ADDP, 1,1'-(azodicarbonyl)dipiperidine.

REFERENCE EXAMPLE 1 3,3,3-triphenylpropanol

Borane-methyl sulfide (60 mL, 0.63 mol) was added dropwise to 100 g(0.33 mol) of 3,3,3-triphenylpropanoic acid and 38 mL (0.33 mol)trimethyl borate in 1 liter of anhydrous tetrahydrofuran at roomtemperature. After 18 hr, the reaction mixture was carefully acidifiedwith 180 mL of conc. hydrochloric acid, stirred for 3 hours and thenfurther diluted with ca. 450 mL of water. The THF layer was collected,the aqueous layer extracted twice with dichloromethane, and the organiclayers combined and dried over magnesium sulfate. The organic solutionwas evaporated to leave a solid, which was recrystallized (two crops)from hexane-dichloromethane to give 83.3 g (87.5%) of the titlecompound, mp 103°-106° C.

REFERENCE EXAMPLE 2 5,5,5-triphenylpentanol

t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirredmixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g,75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4hr, the reaction mixture was filtered through Celite and evaporated togive a yellow oil. The material was purified by distillation to provide4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g,quantitative). To a solution of triphenylmethane (5.10 g, 20.8 mmol) in25 mL of dry THF at -78° C., 13.1 mL (21 mmol) of 1.6M n-butyllithiumwas added dropwise under nitrogen. Shortly thereafter, 4.29 g (19.3mmol) of 4-chlorobutyl t-butyldimethylsilyl ether was added. Afteraddition of water and extraction with hexane, the product was purifiedby chromatography on silica gel with 1:3 dichloromethane-hexane,providing t-butyldimethylsilyl 5,5,5-triphenylpentyl ether as an oil(6.85 g). This material was dissolved in THF (30 mL) and 16 mL of 1.0Mtetrabutylammonium fluoride in THF was added. After 3 hr, the mixturewas acidified with 1N HCl, extracted with three portions of ethylacetate, and the extracts dried over magnesium sulfate and evaporated invacuo. The product was purified by chromatography on silica gel with a10%-20% gradient of ethyl acetate in hexane, providing the titlecompound as a white solid, 3.83 g (63% overall).

REFERENCE EXAMPLE 3 N-(t-butoxycarbonyl)-4-hydroxybenzylamine

Using the method of L. Farber and P. Gradeff, U.S. Pat. No. 4,388,250,4-hydroxybenzaldehyde was reductively aminated to produce 4-hydroxybenzylamine, obtained as a crystalline monohydrate after dilution of thefiltered reaction mixture with water. This material (12 g, 85 mmol) wassuspended in THF (150 mL), cooled in an ice bath, and di-t-butyldicarbonate (19 g, 87 mmol) was added. The mixture was stirredovernight, then concentrated to a viscous oil. Addition of water (250mL) and vigorous stirring overnight converted the oil into a whitepowder, mp 88°-91° C. (21 g).

REFERENCE EXAMPLE 4 N-(t-butoxycarbonyl)-3-hydroxybenzylamine

By the procedure above, but beginning with 3-hydroxybenzaldehyde,3-hydroxybenzylamine was obtained as a tan crystalline solid, mp168°-171° C. after recrystallization from isopropanol. This wasconverted as above into the title compound, obtained as a tan powder, mp79°-81 ° C. after crystallization from hexane-carbon tetrachloride.

REFERENCE EXAMPLE 5 N-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)-ethylamine

Tyramine (5.58 g, 40.7 mmol) was dissolved in 50 mL of THF at 5° C.Di-t-butyl dicarbonate (8.90 g, 40.8 mmol) in 25 mL of THF was addeddropwise. The reaction was allowed to warm to ambient temperatureovernight, then diluted with water, extracted three times with ethylacetate, and the organic extracts dried over MgSO₄ and concentrated invacuo. The crude brown solid, 8.93 g (93%) was used as is.

REFERENCE EXAMPLE 6 N-(t-butoxycarbonyl)-2-(3-hydroxyphenyl)-ethylamine

3-Hydroxyphenethylamine hydrochloride (11.5 g, 66.2 mmol) and 1.0Naqueous sodium bicarbonate (100 mL) were dissolved in 100 mL of THF andcooled to 5° C. Di-t-butyl dicarbonate (14.5 g, 66.2 mmol) in 100 mL ofTHF was added dropwise. The reaction was allowed to warm to ambienttemperature overnight, then diluted with water, extracted three timeswith ethyl acetate, and the organic extracts dried over MgSO₄ andconcentrated in vacuo. The product was recrystallized in two crops fromhexane-dichloromethane to provide 13.9 g (88%) of the title compound asa tan solid, mp 79°-82° C.

REFERENCE EXAMPLE 7 N-(t-butoxycarbonyl)-3-(4-hydroxyphenyl)-propylamine

A mixture of 3-(4-hydroxyphenyl)propionitrile (5.0 g, 34 mmol), 5%rhodium on alumina (0.5 g), methanol (75 mL) and concentrated ammoniumhydroxide solution (25 mL) was shaken under 50 psi hydrogen for 40 hr.Filtration and evaporation of solvent left crude 3-(4-hydroxyphenyl)propylamine as a colorless oil. This oil was dissolved in THF (100 mL)and di-t-butyl dicarbonate (8.5 g, 38 mmol) was added. When the ensuingexothermic reaction and gas evolution ceased, the mixture wasconcentrated to an oil, and chromatographed on silica gel with 1%isopropanol in 5:1 hexane-ethyl acetate. The title compound was obtainedas a colorless gum (5.1 g).

REFERENCE EXAMPLE 8N,N'-Bis(t-butoxycarbonyl)-N"-(4-hydroxyphenyl)methylguanidine

4-hydroxybenzylamine hydrate, prepared as above (5.33 g) andN,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (10.96 g) werecombined in 150 mL THF, and stirred at reflux for 4 hr. The mixture wasconcentrated, and the crude product chromatographed on silica gel with10% ethyl acetate in dichloromethane. Recrystallization frommethanol-water provided the title compound as a white solid, mp187°-189° C. (10 g, 70%).

REFERENCE EXAMPLE 9N,N'-Bis(t-butoxycarbonyl)-N"-(3-hydroxyphenyl)methylguanidine

3-hydroxybenzylamine, prepared as above (1.23 g) andN,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (2.90 g) were combinedin 100 mL DMF, and silver acetate (2.9 g) was added in three portionsover 30 min with mechanical stirring. The mixture became thick and ayellow color developed. After 1 hr, the mixture was diluted with 300 mLwater, and the solids collected by filtration, re-suspended indichloromethane, filtered to remove silver salts, and chromatographed onsilica gel with 10% ethyl acetate in dichloromethane. Recrystallizationprovided the title compound as a white solid, mp 169°-172° C. (dec) (2.2g, 61%).

REFERENCE EXAMPLE 10N,N'-Bis(t-butoxycarbonyl)-N"-2-(4-hydroxy-phenyl)ethylguanidine

A solution of N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (22.4 g,77.3 mmol) is dissolved in 130 mL of THF and added dropwise undernitrogen to 10.6 g (77.3 mmol) of tyramine in 100 mL of THF at 0° C.Reaction reaches completion overnight according to TLC. The solvent isremoved in vacuo. Purification on a silica gel column, elutedsuccessively with 5% EtOAc/Hexane, 15% EtOAc/Hexane, and 35%EtOAc/Hexane, provides the title compound as a white solid, m.p.132°-133° C. (dec.) (21.0 g, 72%).

REFERENCE EXAMPLE 11N,N'-Bis(t-butoxycarbonyl)-N"-3-(4-hydroxy-phenyl)propylguanidine

Silver acetate (1.3 g) was added to a solution of3-(4-hydroxyphenyl)propylamine hydrochloride (1.2 g) andN,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (1.86 g) in DMF (10mL) containing triethylamine (3.0 g). The mixture was stirred for 3 hr,and an additional 1.0 g silver acetate was added. After one hour, themixture was diluted with ethyl acetate, filtered through Celite, washedwith water, dried over magnesium sulfate, and the solution evaporated.Chromatography on silica gel with 20% ethyl acetate in hexane providedthe title compound as a white solid, mp 142°-144° C. (dec) afterrecrystallization from hexane-ethyl acetate (2.1 g, 77%).

EXAMPLE 1 4- 4-(3,3,3-Triphenylpropanoylamino)phenyl!piperazine

To an ice cooled and stirred solution of 4-(4-aminophenyl)piperazine(4.29 g, 24.2 mmol) in dichloromethane (100 mL) containing Et₃ N (7.42mL, 52.5 mmol) was added trifluoroacetic anhydride (7.52 mL, 53.2 mmol)in dichloromethane (25 mL) over a 5 minute period. The mixture wasallowed to warm to room temperature and stirred two days, then stirredwith ice water. The pink solid that separated was isolated byfiltration, washed with dichloromethane, aqueous sodium bicarbonate, andwater, and dried to obtain1-(4-(trifluoroacetamido)phenyl)-4-trifluoroacetylpiperazine (4.09 g,46% , mp 193°-194° C.). To a mixture of this material (0.37 g, 1 mmol )and anhydrous potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (50mL) was added 3,3,3-triphenylpropionyl chloride (0.54 g) and the mixturestirred at 80° C. for two days. With tlc monitoring, four additionallots of the acid chloride (4×0.54 g) and potassium carbonate (4×1.1 g)were added at 3 hr intervals, with continued reflux until completedisappearance of the starting piperazine by tlc. The solvent was removedin vacuo, the residue triturated with methanol, the solids removed byfiltration and the filtrate evaporated to dryness in vacuo. The residuewas stirred with 20% KOH in methanol (15 mL) for 3 hr and thenevaporated to dryness in vacuo. The residue was partitioned betweenwater and ethyl acetate and the organic layer extracted with 2N HCl. Theacid extract was basified with 2N NaOH to pH 9.5 and extracted withethyl acetate. The organic layer was washed with brine, then dried oversodium sulfate and evaporated to dryness to give the title compound as atan solid (0.40 g, 87%), mp 193°-195° C. ¹ H NMR (CDCl₃) δ 7.33 (m,15H),6.89 (d, J=8.9, 2H) 6.73 (d, J=8.9, 2H), 6.26 (s, 1H), 3.70 (s, 2H),3.00 (d, J=10.0, 8H). IR 3056, 1665, 1598, 1515, 1447, 1239, 700 cm⁻¹.MS 462 (MH+). Anal. calcd. for: C₃₁ H₃₁ N₃ O·0.5 H₂ O: C, 79.12; H,6.85; N, 8.93. Found: C, 78.84; H, 6.66; N, 8.64.

EXAMPLE 2 4-4-(3,3,3-Triphenylpropyloxy)phenyl!-1,2,3,6-tetrahydropiperidine

To a stirred suspension of NaH (0.088 g of 60% oil dispersion, 2.2 mmol,washed with pentane) in N-methylpyrrolidine (5 mL ) under a nitrogenatmosphere, was added 4-(4-hydroxyphenyl)-1,2,3,6-tetrahydropiperidine(0.36 g, 2 mmol) and the mixture heated to 60° for ten minutes untileffervescence ceased. To the clear dark solution 3,3,3-triphenylpropylmethanesulfonate in N-methylpyrrolidine (3 mL) was added and thereaction mixture was stirred at 90° C. for two days. Solvent was removedin vacuo at 100° C., and the residue was chromatographed on silica usinga gradient of methanol in dichloromethane containing 0.5% triethylamine.The desired product eluted with 10% methanol, and was obtained as an oil(0.26 g, 29%).The hydrochloride salt was prepared by passing gaseous HClinto an isopropanol soution. Recrystallization from isopropanol-ethergave 0.19 g tan powder, softening at 95°-100° C. and melting at135°-138° C. ¹ H NMR (CDCl₃) δ 9.9 (br s, 2H), 7.33-7.22 (m, 17H),6.70-6.60 (br m, 2H), 5.86 (s, 1H), 3.73 (t, J=7.5, 4H), 3.12.(t, J=7.2,4H), 4.0-2.5 (br hump). IR 3400, 2958, 2279, 1607, 1513, 1494, 1447,1281, 1241, 1183, 1030, 706 cm⁻¹. MS 446 (MH⁺, free base). Anal. calcd.for C₃₂ H₃₁ NO·HCl·3H₂ O: C, 71.69; H, 7.14; N, 2.61. Found: C, 71.65;H, 6.53; N, 2.85.

EXAMPLE 3 2-(4-(3,3,3-triphenylpropoxy)phenyl)ethylamine

N-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)ethylamine (1.3 g) and3,3,3-triphenylpropanol (1.4 g) were coupled by the method of example 5.The product (1.4 g) was dissolved in 15 mL isopropanol containing 1.0 gHCl, and stirred 3 hr at room temperature. A precipitate formed, whichwas collected and recrystallized from ethanol-ether to provide thehydrochloride salt of the title compound as a white solid, mp 163°-165°C., in 66% yield. Anal. calcd. for C₂₉ H₂₉ NO·HCl·0.75 H₂ O: C, 76.13;H, 6.94; N, 3.06. Found: C, 75.99; H, 6.81; N, 3.02.

EXAMPLE 4 4-(3,3,3-triphenylpropoxy)benzylamine

By the method of example 3, N-(t-butoxycarbonyl)-4-hydroxybenzylaminewas converted into the hydrochloride salt of the title compound, mp215°-217° C. Anal. calcd. for C₂₈ H₂₇ NO·HCl·0.5 H₂ O: C, 76.61; H,6.66; N, 3.19. Found: C, 76.86; H, 6.48; N, 3.19.

EXAMPLE 5 N-(2-(4-(3,3,3-triphenylpropoxy)phenyl)ethylguanidine

A solution of 3,3,3-triphenylpropanol (11.54 g, 40 mmol),N,N'-Bis(t-butoxycarbonyl)-N"-2-(4-hydroxyphenyl)ethylguanidine (15.18g, 40 mmol), and triphenyphosphine (1.54 g, 44 mmol) in THF (400 mL) wascooled to -15° C., and a solution of diethyl azodicarboxylate (7.66 g,44 mmol) in 50 mL THF was added dropwise with stirring. The mixture wasallowed to warm to room temperature, and then refluxed for 4 hr. Themixture was concentrated, and the residue taken up in toluene (300 mL).Triphenylphosphine oxide was removed by filtration, and the filtrateconcentrated and chromatographed on silica gel with dichloromethane.N',N'-bis(t-butoxycarbonyl)-N-(2-(4-(3,3,3-triphenylpropoxy)phenyl)ethylguanidinewas obtained as a colorless gum (8.0 g, 31%). This material wasdissolved in isopropanol (50 mL) containing anisole (8 g) and anhydroushydrogen chloride (10 g), and the solution heated until gas evolutionwas observed, at ca. 50° C. The solution was maintained at thistemperature for 15 minutes, then concentrated in vacuo. The residue wasstirred vigorously for two days with a mixture of ethyl acetate (200 mL)and 1.0N aqueous sodium bicarbonate, and the resulting white solidcollected by filtration, and washed with water, acetone, ethyl acetate,and THF, to provide the bicarbonate salt, containing about 0.75equivalents of water, as a white powder, mp 172°-176° C. (dec). Thismaterial was suspended in 250 mL water, and stirred vigorously whileheating to 90° C. Gas evolution was observed, and the solid became gummyfor a time, then once again became powdery. When gas evolution hadceased, the mixture was cooled, and the solid collected by filtrationand dried in vacuo overnight. The title compound was obtained as thecarbonate salt, a white powder, mp 150°-180° C. (dec) with slow heating,180°-183° C. (dec) with rapid heating. Anal. calcd. for C₃₀ H₃₁ N₃O·0.5CH₂ O₃ : C, 76.22; H, 6.71; N, 8.74. Found: C, 75.79; H, 6.68; N,8.87.

EXAMPLE 6 2-(4-(3,3,3-tris(4-chlorophenyl)propoxy-phenyl)ethylamine

3,3,3-Tris(4-chlorophenyl)propionic acid is reduced to thetriarylpropanol with borane as described above. This material isconverted by the method of example 3 into the title compound, obtainedas the hydrochloride salt, mp 132°-135° C. Anal. calcd. for C₂₉ H₂₆ Cl₃NO·HCl·0.25H₂ O: C, 63.12; H, 5.02; N, 2.53. Found: C, 63.13; H, 4.97;N, 2.55.

EXAMPLE 7 2-(3-(3,3,3-triphenylpropoxy)phenyl)ethylamine

By the method of example 3,N-(t-butoxycarbonyl)-2-(3-hydroxyphenyl)ethylamine was converted to thetitle compound, and was then converted to the oxalate salt by combiningwith oxalic acid in ether. Recrystallization from ethyl acetate-etherprovided the title compound as the 0.5 oxalate 0.5 hydrate, a whitesolid, mp 166°-168° C. ¹ H NMR (DMSO-d₆) δ 7.2-7.4 (m, 15H), 7.12 (t,J=7 Hz, 1H), 6.74 (d, J=7 Hz, 1H), 6.5-6.6 (m, 2H), 4.5-5.5 (br s, 4H,--NH₃ + and HOD), 3.66 (t, J=7 Hz, 2H), 3.07 (t, J=7 Hz, 2H), 2.85 (t,J=7 Hz, 2H), 2.65 (t, J=7 Hz, 2H), Anal. calcd. for C₂₉ H₂₉ NO·0.5C₂ H₂O₄ ·0.5H₂ O: C, 78.06; H, 6.77; N, 3.03. Found: C, 78.26; H, 6.73; N,3.13.

EXAMPLE 8 2-(4-methoxy-3-(3,3,3-triphenylpropoxy)-phenyl)ethylamine

Di-t-butyl dicarbonate (1.15 g, 5.25 mmol) was added to a mixture of3-hydroxy-4-methoxyphenethylamine hydrochloride (1.05 g, 5.15 mmol) andtriethylamine (0.521 g, 5.15 mmol) in water (1 mL), dimethylformamide (5mL) and dichloromethane (25 mL). The mixture was stirred at roomtemperature overnight. The organic phase was transferred directly to asilica gel column packed in dichloromethane, and eluted withdichloromethane, then with 10% ethyl acetate in dichloromethane.Evaporation the eluate providedN-(t-butoxy-carbonyl)-2-(3-hydroxy-4-methoxyphenyl)ethylamine, as awhite solid, mp 100°-101° C., after trituration with hexane. By themethod of example 3, this was converted into the title compound,obtained as the hydrochloride salt, a white solid, mp 111°-112° C. ¹ HNMR (DMSO-d₆) δ 7.84 (s, 3H, --NH₃ ⁺), 7.2-7.4 (m, 15H), 6.88 (d, J=8Hz, 1H), 6.74 (dd, J=1 and 8 Hz, 1H), 6.46 (d, J=1 Hz, 1H), 3.72 (s,3H), 3.66 (t, J=7 Hz, 2H), 3.08 (t, J=7 Hz, 2H), 2.90 (t, J=7 Hz, 2H),2.68 (t, J=7 Hz, 2H), Anal. calcd. for C₃₀ H₃₁ NO₂ ·HCl·0.25 H₂ O: C,75.30; H, 6.85; N, 2.93. Found: C, 75.10; H, 6.74; N, 2.80.

EXAMPLE 9N-(2-(4-(3,3,3-tris(4-chlorophenyl)propoxy)-phenyl)ethyl)guanidine

By the method of example 5, 3,3,3-Tris(4-chlorophenyl)propanol isconverted into the title compound, obtained as the bicarbonate salt, awhite solid, mp 146°-150° C. ¹ H NMR (DMSO-d₆) δ 7.39 (d, J=8.7 Hz, 6H),7.28 (d, J=8.7 Hz, 6H), 7.07 (d, J=8.5 Hz, 2H), 6.62 (d, J=8.5 Hz, 2H),3.64 (t, J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H), 3.1-3.5 (br m, 6H), 2.63 (t,J=7 Hz, 2H). Anal. calcd. for C₃₀ H₂₈ Cl₃ N₃ O·CH₂ O₃ : C, 60.55; H,4.92; N, 6.83. Found: C, 60.93; H, 4.80; N, 6.90.

EXAMPLE 10 N-(2-(4-(5,5,5-triphenylpentoxy)phenyl)ethylguanidine

By the method of example 5, 5,5,5-triphenyl-1-pentanol is converted intothe title compound, obtained as the oxalate salt, a white solid, mp119°-121° C. Anal. calcd. for C₃₂ H₃₅ N₃ O·C₂ H₄ O₄ ·0.5H₂ O: C, 70.57;H, 6.97; N, 7.26. Found: C, 70.41; H, 6.63; N, 7.18.

EXAMPLE 11 N-(2-(4-(4,4,4-triphenylbutoxy)phenyl)ethylguanidine

By the method of example 5, 4,4,4-triphenyl-1-butanol is converted intothe title compound, obtained as the bicarbonate salt, a white solid, mp169°-170° C. Anal. calcd. for C₃₁ H₃₃ N₃ O·CH₂ O₃ ·0.5H₂ O: C, 71.89; H,6.79; N, 7.86. Found: C, 71.59; H, 6.64; N, 7.71.

EXAMPLE 12 3- 4-(3,3,3-Triphenylpropoxy)phenyl!propionic acid

To a solution of 3,3,3-triphenylpropanol (2.22 g, 7.70 mmol), methyl3-(4-hydroxyphenyl)propionate (9.40 mmol) and triphenylphosphine (2.42g, 9.23 mmol) in dry THF (25 mL) under a nitrogen atmosphere at roomtemperature, was added dropwise DEAD (1.50 mL, 9.52 mmol) in dry THF (20mL) over approximately 30 minutes. The reaction was heated to refluxovernight. After cooling, the THF was evaporated and the residuechromatographed on a silica column with 5-15% EtOAc/hexanes to affordthe ester as snow white crystals, mp=53°-54° C. (triturated withhexanes), 67% yield. ¹ H NMR (CDCl₃) δ 7.19-7.33 (m, 15H), 7.02 (d,J=8.7 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 3.68 (t, J=7.8 Hz, 2H), 3.64 (s,3H), 3.12 (t, J=7.8 Hz, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.55 (t, J=7.7 Hz,2H). IR 3064, 1737, 1512, 1238 cm⁻¹. MS 451 (MH+), 271 (base). Anal.calcd. for C₃₁ H₃₀ O₃ : C, 82.64; H, 6.71. Found: C, 82.72; H, 6.77.This ester (667 mg, 1.49 mmol) and NaOH (1N, 3.0 mL) in methanol (10 mL)were heated to 60° C. overnight. After cooling, the methanol wasevaporated. The resulting aqueous residue was diluted with water (20 mL)and acidified to pH=1 with conc HCl. The precipitate was collected,washed with water (50 mL) and dried in vacuo. White solid, mp=126°-127°C. (ether/hexanes), 89.5% yield. ¹ H NMR (CDCl₃) δ 7.02-7.25 (m, 15H),6.95 (d, J=8.3 Hz, 2H), 6.55 (d, J=8.3 Hz, 2H), 3.62 (t, J=7.6 Hz, 2H),3.04 (t, J=7.6 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.51 (t, J=7.6 Hz, 2H).IR 2880-3160 (br), 1690 cm⁻¹. MS 437 (MH+). Anal. calcd. for C₃₀ H₂₈ O₃·0.2H₂ O: C, 81.86; H, 6.50. Found: 81.76; H, 6.45.

EXAMPLE 13 2- 4-(3,3,3-Triphenylpropoxy)phenyl!acetic acid

By the method of example 12, methyl (4-hydroxyphenyl)acetate wasconverted to the title compound. White solid, mp=148°-149° C. (ether),72% yield. ¹ H NMR (CDCl₃) δ 7.19-7.34 (m, 15H), 7.10 (d, J=8.6 Hz, 2H),6.65 (d, J=8.6 Hz, 2H), 3.70 (t, J=7.8 Hz, 2H), 3.54 (s, 2H), 3.12 (t,J=7.8 Hz, 2H). IR 3100-2800 (br), 1709, 1514 cm⁻¹. MS 423 (MH+), 243.Anal. calcd. for C₂₉ H₂₆ O₃ : C, 82.44; H, 6.20. Found: C, 82.17; H,6.30.

EXAMPLE 14 3- 4-(3,3,3-Triphenylpropylthio)phenyl!propionic acid

By the method of example 12, but using ADDP instead of DEAD, and n-Bu₃ Pinstead of Ph₃ P, methyl 4-mercaptohydrocinnamate was converted into thetitle compound. Colorless solid, mp=51°-53° C., 67% yield. ¹ H NMR(CDCl₃) δ 9.50 (br s, 1H), 7.08-7.45 (m, 19H), 2.84-2.92 (m, 4H),2.57-2.61 (m, 4H). IR 3500, 1707, 1594, 1492, 1290 cm⁻. MS 453 (MH⁺).Anal. calcd. for C₃₀ H₂₈ O₂ S: C, 79.61; H, 6.24. Found: C, 79.29; H,5.87.

EXAMPLE 15 4- 4-(3,3,3-Triphenylpropoxy)phenyl!butyric acid

By the method of example 12, methyl 4-(4-hydroxyphenyl)butyrate wasconverted to the title compound, obtained as an amorphous solidcontaining residual ethyl acetate. ¹ H NMR (CDCl₃) δ 7.17-7.34 (m, 15H),7.00 (d, J=8.6 Hz, 2H), 6.62 (d, J=8.6 Hz, 2H), 3.69 (t, J=7.8 Hz, 2H),3.12 (t, J=7.8 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.32 (t, J=7.5 Hz, 2H),1.89 (quin., J=7.5 Hz, 2H). IR 3300-2500 (br), 1711, 1512 cm⁻¹. MS 451(MH+), 243. Anal. calcd. for C₃₁ H₃₀ O₃ ·0.05C₄ H₈ O₂ : C, 82.36; H,6.73. Found: C, 82.02; H, 6.71.

EXAMPLE 16 N- 4-(2-Aminoethyl)phenyl!-3,3,3triphenylpropionamide

To 3,3,3-triphenylpropanoic acid (1.0 g, 3.3 mmol) in dry benzene (10mL) under a nitrogen atmosphere at room temperature, was added DMF (2drops) followed by oxalyl chloride (0.29 mL; 3.3 mmol). After stirringfor 1 h, the benzene was evaporated to give acid chloride (1.02 g, 96%yield). To the acid chloride (300 mg; 0.94 mmol) in dichloromethane (15mL) at 0° C. under a nitrogen atmosphere, was added triethylamine (0.26mL; 1.87 mmol). N-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)ethylamine (0.94mmol) in dichloromethane (5 mL) was added dropwise over a 10 minuteperiod. After stirring overnight, the reaction was poured into brine (25mL) and extracted with EtOAc (2×50 mL). The combined organic layers werewashed with water (25 mL), brine (25 mL), dried (MgSO₄), filtered andevaporated. Off-white solid, mp=179°-181° C. (ethanol). ¹ H NMR δ7.26-7.34 (m, 15H), 6.99 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 6.34(s, 1H), 4.45 (br s, 1H), 3.72 (s, 2H), 3.28 (m, 2H), 2.68 (t, J=7.6 Hz,2H), 1.37 (s, 9H). IR 2900-3400 (br), 1678, 1531 cm⁻¹. MS 521 (MH+).Anal. calcd. for C₃₄ H₃₆ N₂ O₃ ·0.2H₂ O: C, 77.89; H, 7.00; N, 5.34.Found: C, 77.64; H, 6.91; N, 5.24. The protected amine (0.50 mmol) wasdissolved in 20%HCl in isopropanol (5 mL) and heated to 80° C. for 30min. After cooling, the precipitate was collected by filtration, washedwith isopropanol, and dried in vacuo. The title compound was obtained asthe hydrochloride monohydrate, a white solid, mp>250° C. (ethanol), in69% yield. ¹ H NMR (DMSO-d₆) δ 9.65 (br s, 1H), 7.82 (br s, 3H),7.16-7.25 (m, 17H), 7.06 (d, J=8.5 Hz, 2H), 3.83 (s, 2H), 2.92-2.95 (m,2H), 2.74-2.77 (m, 2H). IR 2800-3480 (br), 1664, 1515 cm⁻¹. MS 421(MH+), 243. Anal. calcd. for C₂₉ H₂₈ N₂ O·HC·H₂ O: C, 73.33; H, 6.58; N,5.90. Found: C, 73.22; H, 6.56; N, 5.92.

EXAMPLE 17 6-(3,3,3-Triphenylpropoxy)-2-naphthoic acid

6-(3,3,3-Triphenylpropoxy)-2-naphthonitrile, prepared in example 20, wasadded to KOH (1 g) dissolved in ethanol (15 mL). The solution was heatedat reflux under a nitrogen atmosphere for two days. After cooling, theethanol was evaporated and the residue diluted with water. This wasacidified with dilute HCl and extracted with dichloromethane. Theorganic layers were washed with water, dried (MgSO₄), filtered andevaporated, providing the title compound as a colorless solid,mp=243°-244° C. (Et₂ O/pentane), 68% yield. ¹ H NMR (CDCl₃) δ 8.58 (s,1H), 8.02 (m, 1H), 7.82 (d, J=9.0, 1H), 7.64 (d, J=8.7, 1H), 7.20-7.38(m, 15H), 7.11 (dd, J=2.3, 9.0 Hz, 1H), 6.80 (m,1H), 3.91 (m, 2H), 3.21(m, 2H). MS 459 (MH⁺). Anal. calcd. for C₃₂ H₂₆ O₃ : C, 83.82; H, 5.72.Found: C, 83.69; H, 5.63.

EXAMPLE 18 N- 4-(2-Guanidinoethyl)phenyl!-3,3,3-triphenylpropionamide

By the method of example 16,N,N'-bis(t-butoxycarbonyl)-N"-2-(4-hydroxyphenyl)ethylguanidine wasconverted to the title compound, obtained as the bis-hydrochloride salt,a yellow solid, mp=213°-215° C., 81% yield. ¹ H NMR (DMSO-d₆) δ7.39-7.44 (m, 1H), 7.17-7.25 (m, 17H), 7.07 (d, J=8.5 Hz, 2H), 3.82 (s,2H), 3.20-3.27 (m, 2H), 2.61-2.66 (m, 2H). IR 2800-3400 (br), 1659, 1516cm⁻¹. MS 463 (MH+). Anal. calcd. for C₃₀ H₃₀ N₄ O·2HCl: C, 67.29; H,6.02; N, 10.46. Found: C, 67.46; H, 6.16; N, 10.95.

EXAMPLE 19 4.5-Dihydro-2-{2- 4-(3,3,3-triphenylpropoxy)-phenyl!ethyl }oxazole

By the method of example 25, ethanolamine was converted toN-(2-hydroxyethyl)-3- 4-(3,3,3-triphenylpropoxy)-phenyl!propionamide. Tothis amide (400 mg; 0.84 mmol) in EtOAc (15 mL), was added dropwise over5 minutes thionyl chloride (0.20 mL, 2.74 mmol) in EtOAc (2 mL) under anitrogen atmosphere at room temperature. After stirring overnight, theprecipitate was collected and washed with EtOAc to give the titlecompound (354.1 mg; 85% yield) as the hydrochloride monohydrate, a whitepowder. mp=130°-131° C. ¹ H NMR δ 7.19-7.34 (m, 15H), 7.02 (d, J=8.6 Hz,2H), 6.62 (d, J=8.6 Hz, 2H), 3.70 (t, J=7.7 Hz, 2H), 3.53 (br s, 4H),3.12 (t, J=7.7 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.5 Hz, 2H).IR 2954, 1513, 1245 cm⁻¹. MS 462 (MH+), 243. Anal. calcd. for C₃₂ H₃₁NO₂ ·HCl·H₂ O: C, 74.48; H, 6.48; N, 2.71. Found: C, 74.26; H, 6.32; N,2.70.

EXAMPLE 20 6-(3,3,3-Triphenylpropoxy)-2-naphthylmethylamine

6-(3,3,3-Triphenylpropoxy)-2-naphthonitrile was prepared by the methodof example 27 utilizing 6-cyano-2-naphthol, ADDP, and nBu₃ P. Colorlesssolid, mp=207°-208° C. (Et₂ O/hexane), 50% yield. ¹ H NMR (CDCl₃) δ 8.09(s, 1H), 7.72 (d, J=9.0, 1H), 7.63 (s, 1H), 7.50 (dd, J=1.4 and 8.5Hz,1H), 7.20-7.37 (m, 16H), 6.76 (d, J=2.1, 1H), 3.90 (m, 2H), 3.20 (m,2H). IR 2220, 1621, 1602, 1493, 1472, 1396 cm⁻¹. MS 440 (MH+). Anal.calcd. for C₃₂ H₂₅ NO: C, 87.44; H, 5.73; N, 3.19. Found: C, 86.93; H,5.78; N, 3.09. A mixture of the nitrile (0.440 g, 1 mmol) andtetra-n-butylammonium borohydride (0.775 g, 3 mmol) in dichloromethanewas heated to reflux under an atmosphere of nitrogen for 18 h. Thesolvent was removed in vacuo and the residue treated with 10% HCl andrefluxed for 3 h. The reaction mixture was then basified with solid NaOHand the liberated amine was extracted in dichloromethane/benzene. Theorganic extracts were washed with water, dried (Na₂ SO₄), filtered andevaporated to dryness to obtain a solid residue which was converted tothe hydrochloride salt by passing dry HCl gas into a dichloromethanesolution and recrystallizing from dichloromethane/Et₂ O to obtain 0.210g (44%), mp=137-140. ¹ H NMR (CDCl₃) δ 8.44 (s, 2H, exchangeable),7.10-7.47 (m, 19 H), 6.49 (dd, J=2.1 and 8.9 Hz, 1H), 6.44 (d, J=1.7,1H), 3.72 (s, 2H), 3.66 (m, 2H), 3.05 (m, 2H). IR 3422-2600, 1634, 1607,1490, 1475 cm⁻¹. MS 444 (MH⁺). Anal. calcd. for: C₃₂ H₂₉ NO·HCl·0.2 H₂O: C, 79.32; H, 6.34; N, 2.89. Found: C, 79.28; H, 6.41; N, 2.92.

EXAMPLE 21 4-(3,3,3-Triphenylpropoxy)benzoic acid

By the method of example 12, methyl 4-hydroxybenzoate was converted tothe title compound. White solid, mp=201°-202° C. (MeOH/H₂ O), 67% yield.¹ H NMR (DMSO-d₆) δ 7.72 (d, J=8.6 Hz, 2H), 7.20-7.36 (m, 15H), 6.57 (d,J=8.6 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 3.00 (t, J=7.3 Hz, 2H). IR2640-3172 (br), 1674, 1602 cm⁻¹. MS 409 (MH+), 243. Anal. calcd. for C₂₈H₂₄ 0₃ : C, 82.33; H, 5.92. Found: C, 82.04; H, 5.91.

EXAMPLE 22 trans 4-(3,3,3-Triphenylpropoxy)cinnamic acid

By the method of example 12, methyl 4-hydroxycinnamate was converted tothe title compound. White crystals, mp=207°-209° C. (EtOAc/hexanes), 90%yield. ¹ H NMR (CDCl₃) δ 7.68 (d, J=15.9 Hz, 1H), 7.41 (d, J=8.8 Hz,2H), 7.20-7.34 (m, 15H), 6.69 (d, J=8.8 Hz, 2H), 6.27 (d, J=15.9 Hz,1H), 3.75 (t, J=7.7 Hz, 2H), 3.14 (t, J=7.7 Hz, 2H). IR 2900-3400 (br),1688, 1624, 1602, 1173 cm⁻¹. MS 435 (MH+), 243 (base). Anal. calcd. forC₃₀ H₂₆ O₃ ·0.2 H₂ O: C, 82.24; H, 6.07. Found: C, 82.31; H, 6.05.

EXAMPLE 23 3,3,3-Triphenylpropyl 2-(4-hydroxyphenyl)acetate

To triphenylpropanol (3.98 mmol), 4-hydroxyphenylacetic acid (3.98mmol), and triphenylphosphine (4.39 mmol) in dry THF (20 mL) at 0° C.under a nitrogen atmosphere, was added DEAD (4.39 mmol) in dry THF (20mL) over 15 minutes. The reaction was stirred at room temperature for16h and then the THF was evaporated. The residue was chromatographed onsilica gel using 15-30% EtOAc/hexanes. White solid, mp=136°-138° C.(ether), 34% yield. ¹ H NMR δ 7.15-7.27 (m, 15H), 7.10 (d, J=8.5 Hz,2H), 6.77 (d, J=8.5 Hz, 2H), 4.90 (s, 1H), 3.90 (t, J=7.9 Hz, 2H), 3.47(s, 2H), 2.93 (t, J=7.9 Hz, 2H). Anal. calcd. for C₂₉ H₂₆ O₃ : C, 82.44;H, 6.20. Found: C, 82.29; H, 6.24.

EXAMPLE 24 3,3,3-Triphenylpropyl 3-(4-hydroxyphenyl)propionate

By the method of example 23, 3-(4-hydroxyphenyl)propionic acid wasconverted to the title compound. Light yellow solid, mp=105°-107° C.,29% yield. ¹ H NMR δ 7.15-7.30 (m, 15H), 7.05 (d, J=8.5 Hz, 2H), 6.75(d, J=8.5 Hz, 2H), 4.64 (s, 1H, exchangeable), 3.87 (t, J=7.9 Hz, 2H),2.81-2.91 (m, 4H), 2.51 (t, J=7.8 Hz, 2H). IR 3100-3600 (br), 1882 cm⁻¹.MS 437 (MH+). Anal. calcd. for C₃₀ H₂₈ O₃ : C, 82.54; H, 6.46. Found: C,82.09; H, 6.45.

EXAMPLE 25 trans N-(2-Hydroxyethyl)-4-(3,3,3-triphenylpropoxy)-cinnamide

By the method of example 22, methyl 4-(3,3,3-triphenylpropoxy)cinnamatewas prepared. This ester (500 mg; 1.11 mmol) and ethanolamine (1.5 mL)were heated in an oil bath at 100° C. for 3.5 h under a nitrogenatmosphere. After cooling, the reaction was poured into water (100 mL)and extracted with EtOAc (3×75 mL). The organic layers were washed withwater (100 mL), dried (MgSO₄), filtered and evaporated to give the titlecompound as a hemihydrate, a white, fluffy solid, mp=215°-216° C., 60%yield. ¹ H NMR δ 7.53 (d, J=15.5 Hz, 1H), 7.15-7.37 (m, 17H), 6.65 (d,J=8.9 Hz, 2H), 6.25 (d, J=15.5 Hz, 1H), 6.22 (br s, 1H), 3.70-3.77 (m,4H), 3.50-3.55 (m, 2H), 3.12 (t, J=7.7 Hz, 2H). IR 3000-3250 (br), 1662,1624, 1603, 1512 cm⁻¹. MS 478 (MH+). Anal. calcd. for C₃₂ H₃₁ NO₃ ·0.5H₂O: C, 78.99; H, 6.63; N, 2.28. Found: C, 79.10; H, 6.54; N, 2.81.

EXAMPLE 26 4,5-Dihydro-2-{2- 4-(3,3,3-triphenylpropoxy)-phenyl } ethyl}-1,3-oxazine

By the method of example 19, 3-amino-1-propanol was converted into thetitle compound, obtained as the hydrochloride salt, an amorphous solid,mp=60°-63° C. (EtOAc), 78% yield. 1H NMR (DMSO-d₆) δ 7.84 (m, 1H),7.19-7.38 (m, 15H), 6.99 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.6 Hz, 2H), 3.63(t, J=7.6 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.00-3.18 (m, 4H), 2.68 (t,J=7.5 Hz, 2H), 2.28 (t, J=7.5 Hz, 2H), 1.77 (quin, J=6.8 Hz, 2H). IR3030-3300 (br), 1643, 1611, 1511 cm⁻¹. MS 476 (MH+), 243. Anal. calcd.for C₃₃ H₃₃ NO₂ ·HCl·0.5 H₂ O: C, 76.06; H, 6.77; N, 2.69. Found: C,75.98; H, 6.60; N, 2.65.

EXAMPLE 27 5-{2- 4-(3,3,3-Triphenylpropoxy)phenyl!ethyl }-1H-tetrazole

To 3,3,3-triphenylpropanol (8.70 mmol), 3-(4-hydroxyphenyl)propionitrile(9.40 mmol) and triphenylphosphine (2.42 g, 9.23 mmol) in dry THF (25mL) under a nitrogen atmosphere at room temperature, was added dropwiseDEAD (1.50 mL, 9.52 mmol) in dry THF (20 mL) over approximately 30minutes. The reaction was heated to reflux overnight. After cooling, theTHF was evaporated and the residue chromatographed on a silica column,with 15-20% EtOAc/hexanes. White solid, mp=98°-100° C. (ether), 60%yield. ¹ H NMR δ 7.18-7.35 (m, 15H), 7.06 (d, J=8.6 Hz, 2H), 6.67 (d,J=8.6 Hz, 2H), 3.72 (t, J=7.8 Hz, 2H), 3.13 (t, J=7.8 Hz, 2H), 2.85 (t,J=7.3 Hz, 2H), 2.54 (t, J=7.3 Hz, 2H). IR 2243, 1540 cm⁻¹. MS 418 (MH+),243. Anal. calcd. for C₃₀ H₂₇ NO: C, 86.30; H, 6.52; N, 3.35. Found: C,86.07; H, 6.39; N, 3.24. To a solution of trimethyl aluminum (1M inhexanes, 0.57 mL), in toluene (3 mL) at ˜2° C., was addedazidotrimethylsilane (0.569 mmol). A solution of nitrile (0.474 mmol) intoluene (2 mL) was slowly added. The reaction was stirred at 80° C. for72 h. The cooled (0° C.) reaction was added dropwise to HCl (6M, 10 mL)and EtOAc (10 mL). The resulting mixture was extracted with EtOAc (2×50mL). The combined organic layers were dried (MgSO₄), filtered andevaporated. The crude material was triturated with dichloromethane toremove unreacted starting nitrile leaving behind the title compound as ahydrate, a white solid (mp=193°-195° C., 30% yield). ¹ H NMR (DMSO-d₆) δ7.19-7.35 (m, 15H), 7.02 (d, J=8.5 Hz, 2H), 6.58 (d, J=8.5 Hz, 2H), 3.60(t, J=7.4 Hz, 2H), 3.04-3.12 (m, 4H), 2.91 (t, J=7.6 Hz, 2H). IR3300-3450 (br), 1586, 1511 cm⁻¹. MS 461 (MH+), 243. Anal. calcd. for C₃₀H₂₈ N₄ O·0.25H₂ O: C, 77.48; H, 6.18; N, 12.05. Found: C, 77.18; H,5.96; N, 11.71.

EXAMPLE 28 N-Benzyl-N,N-dimethyl-4-(3,3,3-triphenylpropoxy)-phenyl!methyl ammonium chloride

By the method of example 12, 4-hydroxybenzaldehyde was condensed with3,3,3-triphenylpropanol to provide4-(3,3,3-triphenylpropoxy)benzaldehyde, a white solid, mp 127°-130° C.after recrystallization from hexane (58% yield). This material (4.0 g,10.2 mmol) was suspended in ethanol (100 mL), and sodium borohydride(0.2 g, 5.0 mmol) was added. After 3 hr, aqueous 1N HCl was addeddropwise until gas evolution ceased. Precipitated boric acid was removedby filtration, and the filtrate concentrated to a gummy residue. Thiswas partitioned between water and ether, and the ether solution dried(MgSO₄), filtered, and concentrated. The residue was kept under highvacuum overnight to remove solvent, leaving4-(3,3,3-triphenylpropoxy)benzyl alchohol as an amorphous solid (3.9 g,97%). This material (3.9 g, 9.9 mmol) was dissolved in benzene (80 mL),and thionyl chloride (1.0 mL, 14 mmol) was added, followed by five dropsof DMF at 5-minute intervals. The mixture was heated briefly to reflux,cooled, and concentrated to an oil which solidified on standing.Trituration of the solid with cold methanol provided4-(3,3,3-triphenylpropoxy)benzyl chloride as a white powder, mp 91°-95°C. (83%). ¹ H NMR (CDCl₃) δ 7.19-7.35 (m, 17H), 6.66 (d, J=8.7 Hz, 2H),4.51 (s, 2H), 3.72 (t, J=7.8 Hz, 2H), 3.12 (t, J=7.8 Hz, 2H).

A solution of this material (250 mg, 0.60 mmol) and benzyldimethylamine(85 mg, 0.63 mmol) in acetonitrile (10 mL) was heated to 80° C. for 24hr. A solid formed on cooling which was collected, recrystallized fromacetonitrile, and dried at 90° C. under high vacuum. The title compoundwas obtained as a hemihydrate, a white powder, mp 195°-197° C. (dec), in39% yield. ¹ H NMR (CDCl₃) δ 7.61 (dd, J=ca. 8 Hz and ca. 1 Hz, 2H),7.46 (d, J=8.7 Hz, 2H), 7.43-7.20 (m, 18H), 6.70 (d, J=8.7 Hz, 2H), 5.03(s, 2H), 4.99 (s, 2H), 3.72 (t, J=7.7 Hz, 2H), 3.12 (t, J=7.7 Hz, 2H),3.05 (s, 6H). Anal. calcd. for C₃₇ H₃₈ NO·Cl·0.5H₂ O: C, 79.76; H, 7.06;N, 2.51; Cl, 6.36. Found: C, 79.83; H, 7.02; N, 2.49; Cl, 6.47.

EXAMPLE 29 1-{ 4-(3,3,3-triphenylpropoxy)-phenyl!methyl}pyridiniumchloride

A solution of 4-(3,3,3-triphenylpropoxy)benzyl chloride, prepared inexample 28, (210 mg, 0.51 mmol) in pyridine (1.0 mL) was refluxed fortwo minutes, and concentrated. The residue was recrystallized fromacetonitrile-ethyl acetate and dried at 90° under high vacuum for 18hours, providing the title compound as a monohydrate, a white powder, mp155°-159° C. (212 mg, 86%). ¹ H NMR (CDCl₃) δ 9.56 (d, J=7.5 Hz, 2H),8.31 (t, J=7.5 Hz, 1H), 7.94 (t, J=7.5 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H)7.15-7.35 (m, 15H), 6.68 (d, J=8.6 Hz, 2H), 3.68 (t, J=7.7 Hz, 2H), 3.09(t, J=7.7 Hz, 2H). Anal. calcd. for C₃₃ H₃₀ NO·Cl·H₂ O: C, 77.71; H,6.32; N, 2.75; Cl, 6.95. Found: C, 77.47; H, 6.27; N, 2.63; Cl, 6.65.

EXAMPLE 30 1,2-Dimethyl-3-{4-(3,3,3-triphenylpropoxy)-phenyl!methyl}imidazolium chloride

A solution of 4-(3,3,3-triphenylpropoxy)benzyl chloride, prepared inexample 28, (210 mg, 0.51 mmol) and 1,2-dimethylimidazole (50 mg, 0.52mmol) in acetonitrile (2 mL) was heated to 80° C. for 18 hr. The mixturewas cooled, and ethyl acetate (1 mL) was added. Crystallization wasinduced by scratching with a glass rod, and additional ethyl acetate (5mL) was added. The mixture was heated to reflux, cooled, and theprecipitate collected by filtration. Attempts to remove solvent andwater by prolonged heating at 90° C. in vacuo resulted in gradual lossof chlorine. The material was dissolved in ethanol (0.5 mL), and thesolution diluted with aqueous 1N HCl (10 mL). The precipitate wascollected and dried for 2 hr at 70° under high vacuum, to provide thetitle compound as a hydrate: shiny white flakes, losing water and/orchloromethane at 140° C., and melting at 193-196° C. 1H NMR (CDCl₃) δ7.58 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H) 7.15-7.35 (m, 17H), 6.68(d, J=8.6 Hz, 2H), 5.37 (s, 2H), 3.95 (s, 3H), 3.68 (t, J=7.7 Hz, 2H),3.09 (t, J=7.7 Hz, 2H), 2.78 (s, 3H). Anal. calcd. for C₃₃ H₃₃ N₂O·Cl·1.3H₂ O: C, 74.43; H, 6.74; N, 5.26; Cl, 6.66. Found: C, 74.64; H,6.89; N, 5.21; Cl, 6.41.

EXAMPLE 31 4-(3,3,3-Triphenylpropoxy)benzylidene!malonic acid

To triphenylpropanol (6.21 g; 21.53 mmol), p-hydroxybenzaldehyde (3.43g; 28.08 mmol) and triphenylphosphine (6.88 g; 26.23 mmol) in dry THF(75 mL) under a nitrogen atmosphere at room temperature, was addeddropwise over a 30 minute period DEAD (4.2 mL; 26.67 mmol) in dry THF(50 mL). The reaction was heated at reflux for two days. After cooling,the solvent was evaporated in vacuo and the residue chromatographed on asilica column using 5% EtOAc/hexanes. The aldehyde (5.40 g; 64.0% yield)was isolated as white crystals. mp=129°-130° C. ¹ H NMR (CDCl₃) δ 9.83(s, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.19-7.34 (m, 15H), 6.76 (d, J=8.7 Hz,2H), 3.82 (t, J=7.7 Hz, 2H), 3.16 (t, J=7.7 Hz, 2H). IR 3030, 1689, 1594cm⁻¹. MS 393 (MH+), 243. Anal. calcd. for C₂₈ H₂₄ O₂ : C, 85.68; H,6.16. Found: C, 85.30; H, 6.22. A mixture of the benzaldehyde (235 mg,0.5990 mmol) and malonic acid (84 mg; 0.810 mmol) in glacial HOAc (1 mL)was heated in an oil bath at 80° C. under a nitrogen atmosphere for 16h. The resulting white precipitate was collected and washed with water.Recrystallization from methanol/water afforded the title compound as awhite solid (205 mg; 72% yield) mp=208°-209° C. (dec). ¹ H NMR (DMSO-d₆)δ 7.48 (d, J=8.5 Hz, 2H), 7.42 (s, 1H), 7.20-7.38 (m, 15H), 6.75 (d,J=8.5 Hz, 2H), 3.76 (t, J=7.6 Hz, 2H), 3.11 (t, J=7.6 Hz, 2H). ¹³ C NMR(DMSO-d₆) δ 170.0, 167.2, 161.8, 148.2, 140.1 (CH), 133.0 (CH), 130.4(CH), 129.8 (CH), 127.8 (CH), 127.3, 127.0, 116.4 (CH), 67.3 (CH₂),56.6, 40.1 (CH₂). IR 2965-3400 (br), 1733, 1632, 1598, 1510 cm⁻¹. MS 435(MH+-CO₂ H), 243 (base). Anal. calcd. for C₃₁ H₂₆ O₅ : C, 77.81; H,5.48. Found: C, 77.52; H, 5.51.

EXAMPLE 32 5- 4-(3,3,3-Triphenylpropoxy)phenyl!methyl-1H-tetrazole

By the method of example 27, 4-hydroxyphenylacetonitrile was convertedto the intermediate nitrile. To the nitrile (3.47 mmol) in DMF (20 mL)under a nitrogen atmosphere at room temperature, was added ammoniumchloride (10.4 mmol) followed by sodium azide (10.4 mmol). After acatalytic amount of lithium chloride (0.10 weight of nitrile) was added,the reaction was heated to 135° C. for 24 h. The solvent was removed invacuo. The reaction was diluted with water (50 mL), made basic withaqueous NaOH (1N), and then acidified to pH=1 with HCl (1.0N). Theaqueous layer was extracted with EtOAc (3×150 mL). The combined organiclayers were washed with water (3×50 mL), dried (MgSO₄), filtered andevaporated. Light yellow solid, mp=187°-189° C. (recrystallized fromMeOH/H₂ O, 80% yield). ¹ H NMR (DMSO-d₆) δ 7.21-7.34 (m, 15H), 7.10 (d,J=8.6 Hz, 2H), 6.64 (d, J=8.6 Hz, 2H), 4.15 (s, 2H), 3.58-3.64 (m, 2H),3.00-3.07 (m, 2H). IR 3200-3400 (br), 1609, 1510 cm⁻¹. MS 447 (MH+),243. Anal. calcd. for C₂₉ H₂₆ N₄ O: C, 78.00; H, 5.87; N, 12.55. Found:C, 77.60; H, 5.82; N, 12.13.

EXAMPLE 33 N,N,N-Trimethyl-4-(3,3,3-triphenylpropoxy)phenyl!methylammonium chloride

A suspension of 4-(3,3,3-triphenylpropoxy)benzyl chloride, prepared inexample 28, (413 mg, 1.0 mmol) in commercial 33% trimethylamine-ethanolsolution was sealed in a screw-topped culture tube and was heated to 80°C. for 24 hr. The mixture was cooled and the solvent evaporated, and theresidue recrystallized from isopropanol-ethyl acetate to provide thetitle compound as a hydrate, a white powder, mp 224°-225° C. (dec). 1HNMR (CDCl₃) δ 7.43 (d, J=8.7 Hz, 2H) 7.15-7.35 (m, 15H), 6.71 (d, J=8.7Hz, 2H), 4.82 (s, 2H), 3.73 (t, J=7.7 Hz, 2H), 3.31 (s, 9H), 3.13 (t,J=7.7 Hz, 2H). Anal. calcd. for C₃₁ H₃₄ NO·C·1.5H₂ O: C, 74.60; H, 7.47;N, 2.81; Cl, 7.10. Found: C, 74.99; H, 7.49; N, 2.83; Cl, 7.07.

EXAMPLE 34 2- 3-(3,3,3-Triphenylpropoxy)phenyl!acetic acid

By the method of example 12, methyl 2-(3-hydroxyphenyl)acetate wasconverted to the title compound. Light yellow solid, 46°-49° C.(triturated with hexanes). ¹ H NMR (CDCl₃) δ 7.13-7.34 (m, 16H), 6.81(d, J=7.4 Hz, 1H), 6.60 (m, 2H), 3.73 (t, J=7.7 Hz, 2H), 3.56 (s, 2H),3.12 (t, J=7.7 Hz, 2H). IR 2800-3210 (br), 1710 cm⁻. MS 423 (MH+), 243.Anal. calcd. for C₂₉ H₂₆ O₃ : C, 82.44; H, 6.20. Found: C, 82.34; H,6.43.

EXAMPLE 35 3- 3-(3,3,3-Triphenylpropoxy)phenyl!propionic acid

By the method of example 12, methyl 3-(3-hydroxyphenyl)propionate wasconverted to the title compound, an amorphous solid, in 90% yield. ¹ HNMR (CDCl₃) δ 7.09-7.35 (m, 16H), 6.74 (d, J=7.0 Hz, 1H), 6.50-6.55 (m,2H), 3.73 (t, J=7.6 Hz, 2H), 3.13 (t, J=7.6 Hz, 2H), 2.88 (t, J=7.6 Hz,2H), 2.63 (t, J=7.6 Hz, 2H). IR 2800-3200 (br), 1708 cm⁻¹. MS 437 (MH+).Anal. calcd. for C₃₀ H₂₈ O₃ ·0.25 H₂ O: C, 81.70; H, 6.51. Found: C,81.92; H, 6.63.

EXAMPLE 36 2-(3,3,3-Triphenylpropoxy)phenylacetic acid

By the method of example 12, methyl 2-hydroxyphenylacetate was convertedinto the title compound. White solid, mp=79°-80° C. (MeOH/H₂ O), 61%yield. ¹ H NMR (CDCl₃) δ 7.11-7.32 (m, 17H), 6.84 (t, J=7.4 Hz, 1H),6.50 (d, J=8.1 Hz, 1H), 3.74 (t, J=7.6 Hz, 2H), 3.62 (s, 2H), 3.11 (t,J=7.6 Hz, 2H). IR 3350-3450 (br), 1705 cm⁻¹. MS 423 (MH+). Anal. calcd.for C₂₉ H₂₆ O₀₃ ·0.4H₂ O: C, 81.05; H, 6.29. Found: C, 81.08; H, 6.28.

EXAMPLE 37 2- 4-(3,3,3-Triphenylpropoxy)phenyl!glycolic acid

To 3,3,3-triphenylpropanol (6.21 g; 21.53 mmol), p-hydroxybenzaldehyde(3.43 g; 28.08 mmol) and triphenylphosphine (6.88 g; 26.23 mmol) in dryTHF (75 mL) under a nitrogen atmosphere at room temperature, was addeddropwise over a 30 minute period DEAD (4.2 mL; 26.67 mmol) in dry THF(50 mL). The reaction was heated at reflux for two days. After cooling,the solvent was evaporated in vacuo and the residue chromatographed on asilica column using 5% EtOAc/hexanes. The aldehyde (5.40 g; 64% yield)was isolated as white crystals. mp=129°-130° C. ¹ H NMR δ 9.83 (s, 1H),7.74 (d, J=8.7 Hz, 2H), 7.19-7.34 (m, 15H), 6.76 (d, J=8.7 Hz, 2H), 3.82(t, J=7.7 Hz, 2H), 3.16 (t, J=7.7 Hz, 2H). IR 3030, 1689, 1594 cm⁻¹. MS393 (MH+), 243. Anal. calcd. for C₂₈ H₂₄ O₂ : C, 85.68; H, 6.16. Found:C, 85.30; H, 6.22. To this aldehyde (587 mg, 1.50 mmol), lithiumchloride (156 mg; 3.68 mmol), and potassium hydroxide (395 mg; 7.04mmol) in water (2 mL) and 1,4-dioxane (2 mL), was added tribromomethane(0.16 mL; 1.83 mmol). The reaction was heated in an oil bath at 50° C.overnight. The crude reaction was acidified to pH=1 with HCl (1N) andextracted with EtOAc (3×50 mL). The combined organic layers were washedwith water (2×50 mL), dried (MgSO₄), filtered and evaporated to leave aviscous oil. The crude acid was added to a solution of acetyl chloride(0.15 mL) in methanol (3 mL). After stirring overnight at roomtemperature under a nitrogen atmosphere, the methanol was evaporated.The residue was dissolved in ether (75 mL), washed 25 with aqueoussaturated NaHCO₃ (2×50 mL), dried (MgSO₄), filtered and evaporated. Themethyl ester of the title compound (395 mg; 58% yield from the aldehyde)was obtained as a white solid after recrystallization fromether/hexanes, mp 113°-114.5° C. ¹ H NMR δ 7.18-7.34 (m, 17H), 6.68 (d,J=8.7 Hz, 2H), 5.07 (d, J=5.4 Hz, 1H), 3.69-3.74 (m, 5H with 3H singletat δ 3.73), 3.30 (br d, J=5.4 Hz, 1H, exchangeable), 3.12 (t, J=7.7 Hz,2H). IR 3485, 2959, 1730, 1508 cm⁻¹. MS 453 (MH+), 165 (base). Anal.calcd. for C₃₀ H₂₈ O₄ : C, 79.62; H, 6.24. Found: C, 79.43; H, 6.25.This was hydrolyzed by the method of example 12 to yield the titlecompound as a white foam, mp 55°-58° C. (ether/hexanes), 82% yield. ¹ HNMR δ 7.20-7.33 (m, 17H), 6.69 (d, J=8.7 Hz, 2H), 5.14 (s, 1H), 3.72 (t,J=7.7 Hz, 2H), 3.12 (t, J=7.7 Hz, 2H). IR 2900-3500 (br), 1719, 1609,1510 cm⁻¹. MS 439 (MH+), 421 (MH+-H₂ O). Anal. calcd. for C₂₉ H₂₆ O₄·0.75H₂ O: C, 77.06; H, 6.13. Found: C, 77.34; H, 6.12.

EXAMPLE 38 3- 2-(3,3,3-Triphenylpropoxy)phenyl!propionic acid

By the method of example 12, methyl 3-(2-hydroxyphenyl)propionate wasconverted to the title compound. White solid, mp=118°-120° C. (i-PrOH).¹ H NMR δ 7.11-7.35 (m, 16H), 7.06 (t, J=7.8 Hz, 1H), 6.82 (t, J=7.0 Hz,1H), 6.48 (d, J=8.0 Hz, 1H), 5 3.75 (t, J=7.7 Hz, 2H), 3.15 (t, J=7.7Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H). IR 2700-3250(br), 1705 cm⁻¹. MS 437 (MH+), 243. Anal. calcd. for C₃₀ H₂₈ O₃ : C,82.54; H, 6.46. Found: C, 82.35; H, 6.46.

EXAMPLE 39 5- 4-(3,3,3-Triphenylpropoxy)phenyl!-1H-tetrazole

By the method of example 27, 4-hydroxybenzonitrile was converted intothe title compound. White solid, mp=232°-233° C. (triturated withdichloromethane). ¹ H NMR (DMSO-d₆) δ 7.92 (d, J=8.7 Hz, 2H), 7.20-7.36(m, 15H), 6.89 (d, J=8.7 Hz, 2H), 3.79 (t, J=7.1 Hz, 2H), 3.14 (t, J=7.1Hz, 2H). IR 3260-3650 (br), 1616, 1506 cm⁻¹. MS 433 (MH+), 243. Anal.calcd. for C₂₈ H₂₄ N₄ O·0.25H₂ O: C, 76.95; H, 5.65; N, 12.82. Found: C,77.05; H, 5.54; N, 12.68.

EXAMPLE 40 3- 4-(3,3,3-Triphenylpropylthio)phenyl!propylamine

By the method of example 5,N-(t-butoxycarbonyl)-3-(4-mercapto-phenyl)propylamine was converted tothe title compound, obtained as the hydrochloride salt, a tan solid,mp=73°-75° C. Anal. calcd. for C₃₀ H₃₁ NS·HCl·0.5H₂ O: C, 74.58; H,6.88; N, 2.90. Found: C, 74.61; H, 7.02; N, 2.80.

EXAMPLE 41 5- 4-(3,3,3-Triphenylpropoxy)phenyl!thiazolidine-2,4-dione

The intermediate hydroxy ester was prepared by the method stated inexample 37. To the hydroxy ester (225 mg; 0.497 mmol) in benzene (3 mL),was added thionyl choride (48 μl; 0.66 mmol) and pyridine (48 μΛ; 0.59mmol) under a nitrogen atmosphere. After stirring overnight at roomtemperature, the benzene was evaporated. The residue was dissolved inEtOAc (75 mL) and washed with water (2×30 mL), dried (MgSO₄), filteredand evaporated. Chromatography on silica gel with 10% EtOAc/hexanesafforded chloroester as a viscous oil (210 mg; 90% yield). ¹ H NMR δ7.18-7.34 (m, 17H), 6.68 (d, J=8.8 Hz, 2H), 5.29 (s, 1H), 3.71-3.76 (m,5H with 3H singlet at δ 3.74), 3.13 (t, J=7.7 Hz, 2H). Chloroester (210mg; 0.4461 mmol) and thiourea (71.2 mg; 0.9353 mmol) in sulfolane (2 mL)were heated in an oil bath at 110° C. for 4.5 h under a nitrogenatmosphere. The reaction was cooled slightly and aqueous HCl (1N; 2.0mL) was carefully added. The reaction was heated to 100° C. overnight,poured into water (50 mL) and extracted with ether (3×50 mL). Theorganic layers were washed with water (4×25 mL), dried (MgSO₄), filteredand evaporated. The crude product was chromatographed on a silica gelcolumn using 25% EtOAc/hexanes to give title compound (202 mg; 58%yield) as a white foam. mp=85°-87° C. ¹ H NMR δ 8.02 (br s, 1H),7.22-7.31 (m, 17H), 6.70 (d, J=8.6 Hz, 2H), 5.30 (s, 1H), 3.73 (t, J=7.6Hz, 2H), 3.13 (t, J=7.6 Hz, 2H). IR 2950-3200 (br), 1757, 1700, 1510cm⁻¹. MS 480 (MH+). Anal. calcd. for C₃₀ H₂₅ NO₃ S·0.25H₂ O: C, 74.73;H, 5.31; N, 2.89. Found: C, 74.44; H, 5.56; N, 2.73.

EXAMPLE 42 2-Hydroxy-6-(3,3,3-triphenylpropoxy)benzoic acid

By the method of example 12, methyl 2,6-dihydroxybenzoate was convertedinto the methyl ester of the title compound, isolated by chromatographyon silica gel with a gradient of dichloromethane in hexane. This wassaponified to give the title compound, isolated as a hydrate, a whitesolid, mp 167-168° C. after recrystallization from ether-hexanes. ¹ HNMR (CDCl₃) δ 12.13 (s, 1H), 11.38 (s, 1H), 7.21-7.34 (m, 16H), 6.65 (d,J=9 Hz, 1H), 6.10 (d, J=9 Hz, 1H), 4.05 (dd, J=7.9 and7.3 Hz, 2H), 3.20(dd, J=7.9 and 7.3 Hz, 2H). MS m/z 425 (MH+). Anal. calcd. for C₂₈ H₂₄O₀₄ ·0.25H₂ O: C, 78.39; H, 5.76. Found: C, 78.42; H, 5.74.

EXAMPLE 43 trans 3-(3,3,3-Triphenylpropoxy)cinnamic acid

By the method of example 12, methyl 3-hydroxycinnamate was converted tothe title compound, obtained as a hydrate, a white solid, mp=104°-109°C. (water), 98% yield. ¹ H NMR (DMSO-d₆) δ 7.16-7.36 (m, 17H), 7.03-7.09(m, 1H), 6.85 (br s, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.40 (d, J=15.9 Hz,1H), 3.71 (t, J=7.2 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H). IR 3200-3400 (br),1639, 1578 cm⁻¹. MS 435 (MH+), 417 (M-OH)+, 243 (base). Anal. calcd. forC₃₀ H₂₆ O₃ ·1.25 H₂ O: C, 78.84; H, 6.29. Found: C, 78.75; H, 5.96.

EXAMPLE 44 3-(3,3,3-triphenylpropoxy)phenoxyacetic acid

To 3,3,3-triphenylpropanol (2.00 g, 6.93 mmol), triphenyl-phosphine(6.93 mmol), and 3-(benzenesulfonyloxy)phenol (1.74 g, 6.93 mmol) inbenzene (10 mL), was added DEAD (6.93 mmol) in benzene (10 mL). Thereaction was heated at 60° C. for 16 hours. After cooling, the volatileswere evaporated and the residue chromatographed on a silica gel columnusing 1:1 dichloromethane/hexanes. Recrystallization from ether afforded3-(3,3,3-triphenylpropoxy)phenyl benzenesulfonate as a white solid,mp=124°-125° C., in 75% yield. ¹ H NMR (CDCl₃) δ 7.77-7.80 (m, 2H),7.41-7.56 (m, 2H), 7.18-7.32 (m, 16H), 7.08 (t, J=8.2 Hz, 1H), 6.51-6.59(m, 2H), 6.21 (t, J=2.3 Hz, 1H), 3.55 (t, J=7.7 Hz, 2H), 3.05 (t, J=7.7Hz, 2H). IR 3056, 1612, 1582, 1491 cm⁻¹. MS 538 (M+NH₄)+, 521 (MH+),243. Anal. calcd. for C33H₂₈ O₄ S: C, 76.13; H, 5.42. Found: C, 75.58;H, 5.50. Potassium hydroxide (4.69 g, 0.084 mol) in water (6 mL) andmethanol (30 mL) was added to this material (17.4 g, 0.033 mol) inmethanol (80 mL). The reaction was heated at 50° C. for 20 hours,cooled, and poured into water (150 mL), and acidified to pH=1 withconcentrated HCl. This was extracted with several portions of ether. Thecombined ethereal layers were washed with water, dried, filtered andevaporated to afford 3-(3,3,3-triphenylpropoxy)phenol as a whiteamorphous solid, in 96% yield. ¹ H NMR (CDCl₃) δ 7.10-7.33 (m, 15H),7.04 (t, J=8.1 Hz, 1H), 6.34 (dt, J=8.0, 1.0 Hz, 1H), 6.29 (dd, J=2.1,8.5 Hz, 1H), 6.16 (t, J=2.3 Hz, 1H), 4.65 (s, 1H), 3.67-3.74 (m, 2H),3.12 (t, J=7.8 Hz, 2H). IR 3200-3500 (br), 1595, 1492 cm⁻¹. MS (FAB) 381(MH+), 243. Anal. calcd. for C₂₇ H₂₄ O₂ ·0.25H₂ O: C, 84.23; H, 6.41.Found: C, 84.26; H, 6.66. To the above phenol (2.59 mmol) in acetone (15mL), was added potassium carbonate (5.18 mmol) and methyl bromoacetate(2.75 mmol). The reaction was heated at reflux overnight. After cooling,the reaction was filtered through a pad of Celite. The resultingfiltrate was evaporated and the residue dissolved in methylene chloride.This was washed with water, dried (MgSO₄), filtered and evaporated toafford methyl 3-(3,3,3-triphenylpropoxy)phenoxyacetate. White solid,mp=103°-105° C. (ether), 85% yield. ¹ H NMR (CDCl₃) δ 7.17-7.33 (m,15H), 7.09 (t, J=8.2 Hz, 1H), 6.29-6.43 (m, 3H), 4.57 (s, 2H), 3.79 (s,3H), 3.70 (t, J=7.7 Hz, 2H), 3.12 (t, J=7.7 Hz, 2H). IR 1768, 1602, 1152cm⁻¹. MS 453 (MH+), 243. Anal. calcd. for C₃₀ H₂₈ O₄ ·0.2H₂ O: C, 78.99;H, 6.28. Found: C, 79.04; H, 6.18. The hydrolysis of the ester to theacid was performed as described in example 12, providing the titlecompound as a white solid, mp 69°-71° C., in 89% yield. ¹ H NMR (CDCl₃)δ 7.15-7.30 (m, 15H), 6.95 (t, J=8.2 Hz, 1H), 6.25-6.35 (m, 3H), 4.40(s, 2H), 3.74 (t, J=7.7 Hz, 2H), 3.05 (t, J=7.7 Hz, 2H). IR 3000-3200(br), 1719, 1595 cm⁻¹. MS 439 (MH+), 243. Anal. calcd. for C₂₉ H₂₆ O₄·0.7H₂ O: C, 77.21; H, 6.12. Found: C, 77.04; H, 5.88.

EXAMPLE 45 2-(3,3,3-triphenylpropoxy)phenoxyacetic acid

By the method of example 44, 2-(benzenesulfonyloxy)-phenol was convertedto the title compound, a white solid, mp 137°-139° C. (ether), in 62%yield. ¹ H NMR (DMSO-d₆) δ 7.22-7.38 (m, 15H), 6.66-6.79 (m, 3H), 6.51(d, J=8.0 Hz, 1H), 3.62 (t, J=7.6 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H). IR3200-3500 (br), 1625, 1503 cm⁻¹. MS 456 (M+NH4)+, 271, 243.

EXAMPLE 46 4- 3-(3,3,3-triphenylpropoxy)phenoxy!butyric acid

By the method of example 44, ethyl 4-bromobutyrate was converted to thetitle compound, a white solid, mp 53°-55° C., in 88% yield. ¹ H NMR(CDCl₃) δ 7.12-7.29 (m, 15H), 6.96 (t, J=8.2 Hz, 1H), 6.34 (d, J=8.2 Hz,1H), 6.18-6.23 (m, 2H), 3.90-4.20 (br s ,1H), 3.78-3.82 (m, 2H), 3.66(t, J=7.6 Hz, 2H), 3.07 (t, J=7.6 Hz, 2H), 2.36-2.42 (m, 5H). IR3300-3550 (br), 1708, 1593 cm⁻¹. MS 467 (MH+), 243. Anal. calcd. for C₃₁H₃₀ O₄ ·1.0H₂ O: C, 76.84; H, 6.66. Found: C, 76.85; H, 6.55.

EXAMPLE 47 4- 2-(3,3,3-triphenylpropoxy)phenoxy!butyric acid

By the method of example 44, ethyl 4-bromobutyrate was converted to thetitle compound, a white solid, mp 107°-108° C., in 83% yield. ¹ H NMR(CDCl₃) δ 7.16-7.34 (m, 15H), 6.78-6.86 (m, 3H), 6.57 (d, J=7.1 Hz, 1H),4.06 (t, J=6.1 Hz ,2H), 3.76 (t, J=7.9 Hz, 2H), 3.18 (t, J=7.9 Hz, 2H),2.63 (t, J=7.1 Hz, 2H), 2.05-2.17 (m, 2H). IR 2900-3200 (br), 1718, 1507cm⁻¹. MS 467 (MH+), 271, 243. Anal. calcd. for C₃₁ H₃₀ O₄ ·0.6H₂ O: C,78.00; H, 6.59. Found: C, 77.68; H, 6.96.

EXAMPLE 48 4-(3,3,3-triphenylpropoxy)phenoxyacetic acid

4-(3,3,3-Triphenylpropoxy)benzaldehyde (2.16 g, 5.5 mmol), and mCPBA(2.85g, 8.25 mmol) in methylene chloride (60 mL) were heated at refluxunder a nitrogen atmosphere for 4 h. After cooling, the volatiles wereevaporated and the residue dissolved in ether (250 mL). This was washedwith saturated NaHCO₃ (2×150 mL), brine (150 mL), dried (MgSO₄),filtered and evaporated to afford the crude formate. ¹ H NMR (CDCl₃) δ8.25 (s, 1H), 7.20-7.34 (m, 15H), 6.95 (d, J=9.0 Hz, 2H), 6.68 (d, J=9.0Hz, 2H), 3.71 (t, J=7.7 Hz, 2H), 3.13 (t, J=7.7 Hz, 2H). Attempts topurify the formate (florisil chromatography) lead to4-(3,3,3-triphenylpropoxy)phenol which was isolated as an amorphoussolid (57% yield from the aldehyde). ¹ H NMR (CDCl₃) δ 7.16-7.33 (m,15H), 6.67 (d, J=9.0 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 4.35 (s, 1H),3.63-3.68 (m, 2H), 3.10 (t, J=7.8 Hz, 2H). By the method of example 44,methyl bromoacetate was converted into the title compound, a whitesolid, mp 66°-68° C. ¹ H NMR (CDCl₃) δ 7.16-7.32 (m, 15H), 6.76 (d,J=9.1 Hz, 2H), 6.62 (d, J=9.1 Hz, 2H), 4.53 (s, 2H), 3.66 (t, J=7.9 Hz,2H), 3.10 (t, J=7.9 Hz, 2H). Anal. calcd. for C₂₉ H₂₆ O₄ ·0.5H₂ O: C,77.83; H, 6.08. Found: C, 77.79; H, 6.04.

EXAMPLE 49 4- 4-(3,3,3-triphenylpropoxy)phenoxy!butyric acid

By the method of example 48, ethyl 4-bromobutyrate was converted to thetitle compound, mp=138°-139° C.

We claim:
 1. A method of treating bacterial infections in mammals byadministering to a mammal suffering from such infection atherapeutically effective amount of a compound selected from those ofthe formula 1: ##STR20## wherein R is hydrogen,C₁ to C₆ lower alkyl oraryl-C₁ to C₆ alkyl;Z¹, Z², and Z³ are independently H, halogen, C1-C6alkyl, C1-C6 alkoxy, hydroxy, amino, or nitro; m is an integer from 1-5;X is CH₂ O, CH₂ S, CH₂ NR, C(O)NR, CH₂ OC(O)CH₂, or CH₂ OC(O)CH₂ CH₂ ;Ar is aryl optionally substituted with one to three substituents,selected from halogen, hydroxy, C1-C6 alkyl and C1-C6 alkoxy; W isoxygen, sulfur, or a bond; n is an integer from 0-5; A is selected frommoieties of the formulae: ##STR21## aryl is phenyl, biphenyl ornaphthyl; with the proviso that; where n is 0 or 1, W is a bond;and thepharmaceutically acceptable salts and prodrug forms thereof.
 2. A methodaccording to claim 1 wherein X is selected from CH₂ O and CH₂ S.
 3. Amethod according to claim 1 wherein Ar is selected from 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,6-naphthylene, 6,1-naphthylene,1,5-naphthylene, 2,5-naphthylene, 5,2-naphthylene, and 2,6-naphthylene.4. A method according to claim 1 wherein:X is selected from CH₂ O, andCH₂ S; Ar is selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene,1,6-naphthylene, 6,1-naphthylene, 1,5-naphthylene, 2,5-naphthylene,5,2-naphthylene, and 2,6-naphthylene; where Ar may optionally be furthersubstituted with one to three substituents selected from halogen, C1-C6alkyl, hydroxy, and C1-C6 alkoxy; n is 0, 1, 2, or 3; m is 1; W is abond; A is selected from piperidine and tetra-hydropyridine; andaryl isphenyl, biphenyl or naphthyl; and the pharmaceutically acceptable saltsand prodrug forms thereof.
 5. A compound selected from those of theformula 1: ##STR22## wherein R is hydrogen,C₁, to C₆ lower alkyl oraryl-C₁, to C₆ alkyl;Z¹, Z², and Z³ are independently H, halogen, C1-C6alkyl, C1-C6 alkoxy, hydroxy, amino, or nitro; m is an integer from 1-5;X is CH₂ O, CH₂ S, CH₂ NR, C(O)NR, CH₂ OC(O)CH₂, or CH₂ OC(O)CH₂ CH₂ ;Ar is aryl optionally substituted with one to three substituentsselected from halogen, hydroxy, C₁ -C6 alkyl and C ₁ -C6 alkoxy; W isoxygen, sulfur, or a bond; n is an integer from 0-5; A is selected frommoieties of the formulae: ##STR23## aryl is phenyl, biphenyl ornaphthyl; with the proviso that; where n is 0 or 1, W is a bond;and thepharmaceutically acceptable salts and prodrug forms thereof.
 6. Acompound according to claim 5 wherein X is selected from CH₂ O and CH₂S.
 7. A compound according to claim 5 wherein Ar is selected from1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,6-naphthylene,6,1-naphthylene, 1,5-naphthylene, 2,5-naphthylene, 5,2-naphthylene, and2,6-naphthylene.
 8. A compound according to claim 5 wherein:X isselected from CH₂ O, and CH₂ S; Ar is selected from 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,6-naphthylene, 6,1-naphthylene,1,5-naphthylene, 2,5-naphthylene, 5,2-naphthylene, and 2,6-naphthylene;where Ar may optionally be further substituted with one to threesubstituents selected from halogen, C₁ -C6 alkyl, hydroxy, and C 1-C6alkoxy; n is 0, 1, 2, or 3; m is 1; W is a bond; A is selected frompiperidine and tetra-hydropyridine; andaryl is phenyl, biphenyl ornaphthyl; and the pharmaceutically acceptable salts and prodrug formsthereof.
 9. A pharmaceutical composition for treating bacterialinfections comprising an effective amount of a compound selected fromclaim 5 in association with a pharmaceutically acceptable carrier.